GENETICS CBD: powerpoint: genetic imprinting 1. genome 2. histone organization and modifications 3. genomic imprinting 4. prader-willi syndrome 5. angelman syndrome powerpoint: multifactorial congenital malformations 6. multifactorial congenital malformations definition 7. neuropsychiatric disorders and bipolar disease 8. coronary artery disease 9. modifier genes 10. digenic inheritance powerpoint: autosomal recessive inheritance 11. autosomal recessive inheritance definitikn 12. cystic fibrosis 13. marfan syndrome 14. phenylketonuria 15. major phenotypic features for cystic fibrosis powerpoint: chromosomal anomalies 16. chromosomal anomalies definition 17. down syndrome or mongolism 18. jacob’s syndrome 19. Y linked diseases 20. X linked diseases

Reading File

Give all information in details

Finding Sources

Reading File

Searching the Web

Jacob's syndrome XYY karyotype clinical features genetics Y-linked X-linked diseases examples

Searching the Web

Marfan syndrome genetics phenylketonuria PKU autosomal recessive inheritance features modifier genes digenic inheritance

Reading File

Searching the Web

Marfan syndrome FBN1 fibrillin genetics autosomal dominant features aorta lens dislocation

Reading File

Here is the complete, detailed content for all 20 topics across your four PowerPoint presentations:

POWERPOINT 1: GENETIC IMPRINTING

SLIDE 1 - THE GENOME

Definition The genome is the complete set of genetic instructions in a cell - the totality of DNA, including all protein-coding genes, non-coding sequences, regulatory elements, and repetitive sequences.

Key Figures

Human genome: ~3.2 billion base pairs
~20,000-25,000 protein-coding genes
Protein-coding sequences = only ~1.5% of the total genome
~98.5% is non-coding (introns, regulatory regions, repetitive DNA, transposons)

Genome Organization

Nuclear genome: 22 pairs of autosomes + 2 sex chromosomes = 46 chromosomes (diploid)
Mitochondrial genome: ~16,569 bp circular DNA (maternally inherited)
The genome is packaged into chromatin (DNA + histones + non-histone proteins)

Functional Divisions

Component	Function
Exons	Protein-coding sequences
Introns	Non-coding, removed during splicing
Promoters/Enhancers	Regulate gene expression
Repetitive DNA	Structural; some has regulatory roles
lncRNAs / miRNAs	Non-coding RNA with regulatory functions

Genomic Variation

SNPs (single nucleotide polymorphisms): ~10 million in the human genome
CNVs (copy number variants): deletions/duplications >1kb; major source of inter-individual variation
Indels, microsatellites, transposable elements also contribute

Source: Thompson & Thompson Genetics and Genomics in Medicine, 9th ed.; Emery's Elements of Medical Genetics and Genomics

SLIDE 2 - HISTONE ORGANIZATION AND MODIFICATIONS

Chromatin Structure

DNA is wound around octamers of histone proteins (H2A, H2B, H3, H4 - 2 copies each) forming the nucleosome core particle
147 bp of DNA wrap ~1.65 turns around each histone octamer
H1 linker histone seals the DNA at the exit/entry point and assists in higher-order compaction
Nucleosomes are further compacted into 30nm fibers, loops, and ultimately metaphase chromosomes

Levels of Chromatin

Level	Structure	State
Euchromatin	Loosely packed, bead-on-string	Transcriptionally active
Heterochromatin	Tightly compacted	Transcriptionally silenced
Constitutive heterochromatin	Permanently condensed (centromeres, telomeres)	Always silent
Facultative heterochromatin	Conditionally silenced	Can be reactivated

Histone Modifications (Epigenetic Marks) Histones have flexible N-terminal tails that project outward and can be covalently modified post-translationally:

Modification	Enzyme	Effect on Transcription
Acetylation (H3K9ac, H3K27ac)	Histone acetyltransferases (HATs)	Activation - opens chromatin
Deacetylation	Histone deacetylases (HDACs)	Repression - closes chromatin
Methylation (H3K4me3)	Histone methyltransferases	Activation (active promoters)
Methylation (H3K27me3, H3K9me3)	PRC2, SUV39H	Repression
Phosphorylation (H3S10)	Aurora kinases	Chromosome condensation during mitosis
Ubiquitination (H2BK120ub)	RNF20/40	Elongation of transcription
Sumoylation	SUMO ligases	Repression

Histone Code Hypothesis Combinations of modifications at multiple residues act as a "code" read by effector proteins to determine transcriptional output. For example:

H3K4me3 + H3K27ac = active transcription start site
H3K9me3 = constitutive heterochromatin
H3K27me3 = polycomb-mediated silencing

Clinical Relevance

Abnormal histone acetylation is common in malignancies
HDAC inhibitors (e.g., vorinostat, romidepsin) are used in cancer therapy
Loss of H3K27me3 marks is seen in diffuse midline gliomas (H3K27M mutation)

Source: Rheumatology 2-Volume Set 2022; Fitzpatrick's Dermatology; Harrison's Principles of Internal Medicine 22E

SLIDE 3 - GENOMIC IMPRINTING

Definition Genomic imprinting is an epigenetic phenomenon whereby a gene is expressed in a parent-of-origin-specific manner - meaning only the maternal allele or only the paternal allele is expressed in a given tissue, regardless of DNA sequence.

Key Mechanism: DNA Methylation

Methylation occurs primarily at CpG dinucleotides (cytosine-phosphate-guanine sites)
The imprint (methyl mark) is applied to specific DNA sequences during gametogenesis
Differentially Methylated Regions (DMRs) control which allele is silenced
Imprinting Control Regions (ICRs) coordinate expression across entire imprinted domains

Scale

Fewer than 200 human genes are imprinted (estimated)
Most are clustered in imprinted domains, some spanning >1 Mb
Key imprinted clusters: chromosome 15q11-q13, chromosome 11p15

How Imprinting Works

During gametogenesis, the maternal and paternal alleles acquire different epigenetic marks (methylation patterns)
After fertilization, the soma maintains these parent-specific marks through all cell divisions
In the germline of the offspring, the parental imprints are erased and reset according to the sex of the new individual

Consequences of Imprinting Disruption

Disruption	Result
Deletion of paternal allele (chr 15)	Prader-Willi syndrome
Deletion of maternal allele (chr 15)	Angelman syndrome
Maternal UPD (chr 15)	Prader-Willi syndrome
Paternal UPD (chr 15)	Angelman syndrome
Paternal UPD (chr 11p)	Beckwith-Wiedemann syndrome

Uniparental Disomy (UPD)

Uniparental disomy = both copies of a chromosome pair inherited from the same parent
Isodisomy: two identical copies (nondisjunction in meiosis II)
Heterodisomy: two different homologs from same parent (nondisjunction in meiosis I)
UPD for an imprinted chromosome has the same phenotypic effect as a deletion on the opposite parental chromosome

Source: Thompson & Thompson Genetics 9th ed., p.113-115; Emery's Elements of Medical Genetics; Tietz Textbook of Laboratory Medicine 7th ed.

SLIDE 4 - PRADER-WILLI SYNDROME (PWS)

Definition / Overview

Incidence: ~1 in 20,000 births
Result of loss of paternally expressed genes on chromosome 15q11.2-q13

Genetic Mechanisms

Mechanism	Frequency
Paternal deletion of 15q11.2-q13	~70-75%
Maternal uniparental disomy (UPD) of chr 15	~20-25%
Imprinting center (IC) defect	~1-3%
Balanced chromosomal rearrangement	rare

The SNRPN gene and adjacent snoRNA genes (SNURF/SNRPN cluster, MKRN3) are paternally expressed and lost in PWS
Functionally: patients only have maternally derived genetic information at 15q11-q13

Clinical Features

Neonatal period: marked hypotonia, feeding difficulties, failure to thrive
Infancy/childhood: hyperphagia (insatiable appetite) leading to progressive obesity
Short stature with small hands and feet
Hypogonadism (cryptorchidism in males; hypoplastic labia/clitoris in females)
Mild to moderate intellectual disability
Characteristic facial features: almond-shaped eyes, narrow bifrontal diameter, downturned mouth
Behavioral problems: temper tantrums, obsessive-compulsive behaviors, skin picking

Diagnosis

DNA methylation analysis of 15q11-q13 (SNRPN locus) - detects ~99% of cases
FISH or chromosomal microarray for deletion detection
MS-MLPA or microsatellite analysis for UPD

Source: Emery's Elements of Medical Genetics, p.79; Thompson & Thompson Genetics 9th ed., p.114; Henry's Clinical Diagnosis 35th ed.

SLIDE 5 - ANGELMAN SYNDROME (AS)

Definition / Overview

Incidence: ~1 in 15,000 births
Caused by loss of maternally expressed genes on chromosome 15q11-q13 - specifically UBE3A

Genetic Mechanisms

Mechanism	Frequency
Maternal deletion of 15q11.2-q13	~75%
Paternal UPD of chr 15	~5%
IC defect (imprinting center mutation)	~2-3%
UBE3A point mutation	~10%
Unknown mechanism	~10%

Key Gene: UBE3A

Encodes ubiquitin-protein ligase E3A
Imprinted exclusively in the brain (hippocampus, Purkinje cells of cerebellum)
In the brain, only the maternal copy is expressed - the paternal copy is silenced by antisense RNA from the SNURF/SNRPN locus
Loss of maternal UBE3A = Angelman syndrome
Mechanism: ubiquitin-mediated protein destruction in CNS development is disrupted

Clinical Features (the "happy puppet" syndrome)

Severe intellectual disability
Absent or near-absent speech (severe expressive language deficit)
Epilepsy (seizures, often severe; EEG shows characteristic pattern)
Ataxic gait (unsteady, jerky movements)
Happy, excitable demeanor with frequent inappropriate laughter and smiling
Fascination with water
Microcephaly (postnatal)
Fair pigmentation (relative to family)
Wide-spaced teeth, tongue protrusion
Characteristic facial appearance: wide mouth, widely spaced teeth, large lower jaw

Differentiation from PWS

Feature	Prader-Willi	Angelman
Chromosome 15	Paternal deletion/loss	Maternal deletion/loss
Key gene	SNRPN cluster	UBE3A
Intellectual disability	Mild-moderate	Severe
Obesity	Yes	No
Seizures	Rare	Prominent
Behavior	OCD, irritability	Happy, excitable
Speech	Present (reduced)	Absent/minimal

Source: Emery's Elements of Medical Genetics, p.80; Thompson & Thompson Genetics 9th ed., p.114-115

POWERPOINT 2: MULTIFACTORIAL CONGENITAL MALFORMATIONS

SLIDE 6 - MULTIFACTORIAL CONGENITAL MALFORMATIONS: DEFINITION

Definition Multifactorial inheritance refers to conditions caused by the interaction of multiple genes (polygenic) with environmental factors. No single gene or environmental factor alone is sufficient to cause the malformation - it is the combined threshold effect that produces the phenotype.

Threshold Model

The underlying genetic liability follows a normal (Gaussian) distribution in the population
Individuals with liability exceeding a certain threshold develop the malformation
Different thresholds for males vs females explain sex differences in prevalence (e.g., pyloric stenosis is 5x more common in males; congenital dislocation of hip is more common in females)

Characteristics of Multifactorial Inheritance

Recurrence risk is higher in first-degree relatives (siblings, parents, children) than the general population
Risk drops rapidly with decreasing degree of relationship (unlike single-gene disorders)
Risk is higher if multiple family members are affected
Risk is higher if the proband is of the less commonly affected sex (Carter effect)
More severe the malformation, higher the recurrence risk
No clear Mendelian pattern

Common Multifactorial Congenital Malformations

Malformation	Approx. Population Incidence (per 1000)
Cleft lip ± cleft palate	0.4-1.7
Cleft palate alone	0.4
Congenital dislocation of hip	2 (per 1000 females)
Congenital heart defects (all types)	4-8
Ventricular septal defect	1.7
Atrial septal defect	1.0
Patent ductus arteriosus	0.5
Neural tube defects (spina bifida, anencephaly)	2-10 (variable by region)
Pyloric stenosis	5 (per 1000 males)

Congenital Heart Defects (CHD) - Special Focus CHDs are the most common serious birth defect. 5 main developmental subtypes:

Flow lesions (~50% of all CHD): hypoplastic left heart, coarctation of aorta, ASDs, pulmonary stenosis, VSD
Defects in cell migration
Defects in cell death
Abnormalities in extracellular matrix
Defects in targeted growth

Source: Thompson & Thompson Genetics 9th ed., p.181-182; Emery's Elements of Medical Genetics; Robbins & Kumar Basic Pathology

SLIDE 7 - NEUROPSYCHIATRIC DISORDERS AND BIPOLAR DISEASE

Overview Mental illnesses affect ~4% of the human population worldwide. The two most severe categories are schizophrenia and bipolar disorder (manic-depressive illness). Annual cost of care >$200 billion/year in the US alone.

SCHIZOPHRENIA

Prevalence: 1% of the world's population
Onset: typically late adolescence or young adulthood
Features: disordered thought, emotion, social relationships; delusions; hallucinations; disordered mood

Genetic Evidence for Schizophrenia

Relationship	Recurrence Risk (%)	Relative Risk (λ)
Child of two schizophrenic parents	46	23
Child of one affected parent	9-16	11.5
Sibling	8-14	11
Nephew / niece	1-4	2.5
Uncle / aunt	2	2
First cousin	2-6	4
General population	1	1

MZ twin concordance: 40-60%
DZ twin concordance: 10-16%
Chromosomal association: ~25% of individuals with 22q11 deletion (velocardiofacial syndrome) develop schizophrenia

BIPOLAR DISORDER (Manic-Depressive Illness)

Prevalence: ~1-2% worldwide
Characterized by cycles of mania and depression
Strong familial aggregation
MZ twin concordance: ~40-70%
DZ twin concordance: ~15-25%
Heritability: ~70-80%
First-degree relatives of bipolar patients: ~10-fold increased risk vs general population

Genetics of Bipolar Disorder

Polygenic, with hundreds to thousands of contributing variants
GWAS has identified loci in genes including: CACNA1C, ANK3, NCAN, TRANK1, SYNE1
Overlap with schizophrenia: shared genetic architecture (cross-disorder genetics)
De novo CNVs implicated in a subset of cases
Gene-environment interaction: childhood trauma, sleep disruption are key environmental triggers

Treatment Genetics

Lithium response is itself partly heritable (GWAS loci identified near GNG7, NCAN)

Source: Thompson & Thompson Genetics 9th ed., p.182-183

SLIDE 8 - CORONARY ARTERY DISEASE (CAD)

Definition Coronary artery disease is a complex, multifactorial disease caused by atherosclerosis of the coronary arteries. It is the leading cause of death globally.

Genetic Evidence

Heritability of fatal MI: ~56% (from twin studies)
MZ twin concordance for fatal MI: 39% (males), 44% (females)
DZ twin concordance for fatal MI: 26% (males), 14% (females)
A male MZ twin has a 6-8-fold increased risk if his co-twin had early fatal MI
A female MZ twin has a 15-fold increased risk

Stepwise Development - Genetic Factors at Each Stage Genes involved in:

Lipid transport and metabolism - APOE, APOC3, LDLR (LDL receptor), LPA (lipoprotein(a))
- Familial hypercholesterolemia: LDLR mutations (autosomal dominant) dramatically raise LDL and CAD risk
- Elevated LDL is a quantitative trait with significant heritability
Vasoactivity - ACE (angiotensin-converting enzyme), AGTR1
Coagulation - Factor V Leiden (Factor V R506Q), prothrombin G20210A
Inflammation - IL-6, CRP, TNF-alpha loci
Endothelial function - NOS3 (endothelial nitric oxide synthase)

Environmental Factors (interact with genes)

Diet (saturated fat, trans fats)
Physical inactivity
Smoking
Obesity and diabetes mellitus
Systemic inflammation

GWAS Findings

Over 300 loci identified for CAD by genome-wide association studies
9p21.3 locus: first and strongest replicated CAD risk locus; near CDKN2A/CDKN2B
Most individual loci confer small effects; aggregate polygenic risk scores (PRS) show clinical utility

Intermediate Traits

Hypertension, hyperlipidemia, diabetes, and obesity are all intermediate traits with their own genetic architectures that compound CAD risk

Source: Thompson & Thompson Genetics 9th ed., p.183-184; Goldman-Cecil Medicine

SLIDE 9 - MODIFIER GENES

Definition Modifier genes are genes whose allelic variants affect the expression, severity, or phenotypic manifestations of a disease caused by mutations in a different (primary) gene. They do not cause the disease themselves but modulate its course.

Concept

Even classic Mendelian single-gene disorders show variable expressivity partly due to modifier genes
Modifiers can affect: age of onset, severity of specific organ involvement, rate of progression, response to treatment

Classic Example: Cystic Fibrosis (CF) The primary gene is CFTR, but:

Pancreatic insufficiency: explained well by CFTR genotype (Class I/II mutations = severe)
Pulmonary disease severity: poorly explained by CFTR genotype alone
- Heritability of lung disease severity (FEV1%) in CF: ~50% (from MZ vs DZ twin studies in CF patients)
- Two confirmed modifier loci:
  1. MBL2 (mannose-binding lectin): Low MBL2 alleles → reduced innate immunity → worse Pseudomonas containment → worse pulmonary outcomes
  2. TGFB1 (transforming growth factor-beta): High TGFβ alleles → increased lung fibrosis after inflammation → worse FEV1 decline

Other Examples

Primary Disease	Modifier Gene	Effect
Cystic fibrosis	MBL2	Pulmonary severity
Cystic fibrosis	TGFB1	Pulmonary severity
Sickle cell disease	HBF (fetal hemoglobin regulators)	Severity of crises
Familial hypercholesterolemia	APOE	Cardiovascular severity
Huntington disease	MSH3 (DNA mismatch repair)	Age of onset

Significance for Genetics Counseling

Same primary mutation can produce very different phenotypes in different patients
Modifier genes explain variable expressivity within families
Identification of modifier genes offers potential drug targets (e.g., targeting TGFβ pathway in CF)

Source: Thompson & Thompson Genetics 9th ed., p.185

SLIDE 10 - DIGENIC INHERITANCE

Definition Digenic inheritance is the simplest form of multigenic inheritance - a disease requires pathogenic mutations in two different genes (at two different loci) to manifest the full phenotype. Heterozygous variants at each locus alone are insufficient to cause disease; only the combination of both mutations causes the disease.

Characteristics

Neither mutation alone is disease-causing (each heterozygote is asymptomatic or subclinical)
Disease only appears when both mutations are inherited together
Pedigree analysis shows seemingly "autosomal recessive-like" or "sporadic" patterns
Can masquerade as de novo or complex disease

Classic Examples

Digenic Retinitis Pigmentosa
- Mutations in ROM1 + PRPH2 (peripherin) together cause RP
- Heterozygous ROM1 alone = normal; heterozygous PRPH2 alone = normal
- Compound heterozygotes for both = retinitis pigmentosa
Digenic Waardenburg Syndrome Type III
- Combination of PAX3 heterozygosity + MITF heterozygosity
Bartter Syndrome Type V / Digenic BSND
Bardet-Biedl Syndrome (triallelic/tridigenic)
- Some cases involve mutations at two BBS loci
- Illustrates extension to oligogenic inheritance

Inheritance Pattern

Parents who are each heterozygous at different loci are unaffected
Children who inherit both mutations (25% chance if parents carry at different loci) are affected
Distinguish from AR inheritance: AR requires two mutations at the same locus; digenic requires one mutation at each of two different loci

Clinical Significance

Explains sporadic cases in consanguineous families
Explains cases where only one parent is a carrier of a known disease mutation
Example from CF: a child had CF born to a couple where only the mother was a carrier - due to paternal UPD for chromosome 7 (not true digenic but similar principle)
Important for genomic sequencing interpretation: variants of uncertain significance at two loci may be acting diigenically

Source: Emery's Elements of Medical Genetics (citing Schäffer AA, J Med Genet 2013); Thompson & Thompson Genetics 9th ed.

POWERPOINT 3: AUTOSOMAL RECESSIVE INHERITANCE

SLIDE 11 - AUTOSOMAL RECESSIVE INHERITANCE: DEFINITION

Definition Autosomal recessive (AR) inheritance is the pattern in which two pathogenic alleles (one from each parent) at the same autosomal locus are required for the phenotype to be expressed. Heterozygous individuals ("carriers") are clinically unaffected.

Key Characteristics of AR Inheritance

Both sexes affected equally - the gene is autosomal, not sex-linked
Parents of an affected individual are typically unaffected carriers (Aa x Aa)
Carrier × Carrier cross yields:
- 25% homozygous affected (aa)
- 50% heterozygous carriers (Aa) - unaffected
- 25% homozygous normal (AA) - unaffected
Horizontal pattern: affected individuals appear in one generation (siblings), not vertical across generations
Consanguinity increases risk: related parents share more alleles identical by descent (IBD)
Rare diseases are enriched in isolated or consanguineous populations

Pedigree Rules

Unaffected parents → affected child = AR (not AD)
Skip generations is typical
Both sexes affected equally (unlike X-linked)
If parents are related → think AR

Molecular Basis

Homozygous loss-of-function: both alleles produce non-functional protein (most common)
Compound heterozygosity: two different pathogenic alleles at the same locus (e.g., one deletion + one missense)
Pseudodominance: can appear dominant if carrier marries affected individual

Carrier Frequency Estimation Using Hardy-Weinberg equilibrium:

If disease frequency = q² (e.g., CF: 1/2500), then q = 1/50
Carrier frequency = 2pq ≈ 2q = 1/25 (approximately 4% in Northern Europeans)

Source: Goldman-Cecil Medicine; Basic Medical Biochemistry 6th ed.; Dermatology 2-Volume Set 5th ed.

SLIDE 12 - CYSTIC FIBROSIS

Definition Cystic fibrosis is the most common life-shortening autosomal recessive genetic disease in White (Northern European) populations. It is caused by absent or reduced function of the CFTR (Cystic Fibrosis Transmembrane conductance Regulator) protein.

Genetics

Gene: CFTR (chromosome 7q31.2)
CFTR protein: 1480 amino acids; ABC (ATP-binding cassette) transporter superfamily
Most common mutation: F508del (deletion of phenylalanine at position 508, codon 508) - present in ~70% of all CF patients (at least one allele)
Over 2000 CFTR variants identified

CFTR Mutation Classes

Class	Defect	Common Mutations
I	No synthesis / premature stop	W1282X, G542X, R563X
II	Protein misfolding / degradation	F508del, N1303K
III	Defective gating / regulation	G551D, G551S, G1349D
IV	Reduced chloride conductance	R117H, R334W, R347P
V	Reduced transcription / splicing	3849+10kbC→T
VI	Unstable protein / reduced surface expression	4326delTC

Epidemiology

Northern Europe / Americas: 1:2,500-3,000 live births
US prevalence: ~1:10,000 (~35,000 cases)
Hispanic Americans: ~1:7,000
African Americans: ~1:12,000
Rare in Africa and Asia

Pathophysiology by Organ System

Lungs:

CFTR normally secretes Cl⁻/HCO₃⁻ into airway lumen while reducing Na⁺ absorption
In CF: reduced Cl⁻/HCO₃⁻ secretion + increased Na⁺ absorption → airway surface dehydration
Dehydrated, thick mucus → impaired mucociliary clearance → mucus plugging
Chronic bacterial infection: Staphylococcus aureus (early), Pseudomonas aeruginosa (later, most damaging)
Biofilm formation → antibiotic resistance
Chronic neutrophil inflammation → elastase release → bronchiectasis, airway destruction

Sweat Glands:

Sweat Cl⁻ ≥60 mEq/L (diagnostic threshold)
Normal: <20 mEq/L
Mechanism: CFTR normally reabsorbs NaCl as sweat travels to skin; lost in CF → isotonic sweat

Pancreas:

Exocrine pancreas: ducts cannot secrete bicarbonate/chloride → viscous secretions → autodigestion
Pancreatic insufficiency → malabsorption, fat-soluble vitamin deficiency (A, D, E, K)
Endocrine pancreas: progressive fibrosis → CF-related diabetes mellitus (CFRD)

Liver:

Biliary canaliculi obstruction → hepatic fibrosis → cirrhosis in ~5% of patients

Intestine:

Meconium ileus in newborns (15-20%)
Distal intestinal obstruction syndrome (DIOS) in older patients

Reproductive:

Males: congenital bilateral absence of vas deferens (CBAVD) → obstructive azoospermia → infertility (>95%)
Females: thick cervical mucus → reduced fertility

Source: Goldman-Cecil Medicine, p.3231-3290; Medical Physiology; Harrison's Principles 22E

SLIDE 13 - MARFAN SYNDROME

Note: Marfan syndrome is actually an autosomal dominant disorder. It is included here for comparison and to illustrate how a single-gene connective tissue disorder can present.

Definition Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with pleiotropic manifestations affecting primarily the cardiovascular, skeletal, and ocular systems.

Genetics

Gene: FBN1 (fibrillin-1), chromosome 15q21.1
Inheritance: Autosomal dominant (heterozygous pathogenic variant sufficient)
~75% of cases: inherited from affected parent
~25%: de novo mutation in a parent's egg or sperm
FBN1 encodes the glycoprotein fibrillin-1, a major building block of extracellular microfibrils

Pathophysiology

Fibrillin-1 is required for:
1. Structural integrity of the aortic wall, lens zonules, ligaments, lung airways, spinal dura
2. Regulation of TGF-β bioavailability (fibrillin sequesters TGF-β in ECM)
Mutant fibrillin-1 → weakened microfibrils → structural fragility + excess TGF-β signaling → aortic wall degradation and progressive dilatation

Cardinal Clinical Features (Ghent Criteria 2010) Cardiovascular (most dangerous):

Aortic root dilatation/aneurysm (Z-score ≥2.0) - most dangerous
Aortic dissection (Type A - emergency)
Mitral valve prolapse with/without regurgitation
Pulmonary artery dilatation

Ocular:

Ectopia lentis (lens subluxation) - upward displacement in 50-80%
High myopia
Increased risk of retinal detachment, glaucoma, cataracts

Skeletal:

Tall stature with disproportionately long limbs (dolichostenomelia)
Arachnodactyly (long, spider-like fingers; positive wrist and thumb signs)
Pectus excavatum or carinatum
Scoliosis
High, narrow palate
Flat feet
Joint hypermobility

Other:

Dural ectasia (widening of dural sac at lumbar spine)
Stretch marks (striae atrophicae)
Spontaneous pneumothorax

Diagnosis (Ghent 2010) Any one of:

Aortic root dilatation + ectopia lentis
Aortic root dilatation + FBN1 pathogenic variant
Ectopia lentis + FBN1 pathogenic variant (associated with aortic disease)
Systemic score ≥7 + aortic disease

Management

Beta-blockers (atenolol) or losartan (anti-TGF-β) to slow aortic dilatation
Elective aortic root repair when diameter reaches 4.5-5.0 cm
Annual echocardiography
Contact sports and high-intensity exercise restriction

Source: GeneReviews NBK1335; Medscape; Emery's Elements of Medical Genetics

SLIDE 14 - PHENYLKETONURIA (PKU)

Definition Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency of the enzyme phenylalanine hydroxylase (PAH). It leads to accumulation of phenylalanine in blood, brain, and CSF.

Genetics

Gene: PAH (phenylalanine hydroxylase), chromosome 12q23.2
AR inheritance: homozygous or compound heterozygous PAH mutations required
Gene structure: 90 kb, 13 exons, 1359 bp coding sequence → 452 amino acid protein (52 kDa)
Over 1000 PAH variants described; classic PKU typically due to severe loss-of-function mutations
Rare variant: Tetrahydrobiopterin (BH4) deficiency → similar phenotype (hyperphenylalaninemia)

Epidemiology

Global prevalence: ~1:24,000 births
Regional variation: Turkey highest (~38:100,000); Eastern Europe ~1:7,000; US ~1:10,000-15,000; Thailand lowest (~0.3:100,000)

Biochemical Defect

Normal: phenylalanine → tyrosine (via PAH + cofactor BH4)
In PKU: PAH absent/deficient → phenylalanine accumulates → converted to phenylpyruvate, phenylacetate, phenyllactate
These metabolites are neurotoxic; phenylalanine competes with other large neutral amino acids at the blood-brain barrier

Clinical Phenotypes (without treatment)

Phenotype	Plasma Phe (µmol/L)	Intelligence Impact
Classic PKU	>1200	Severe intellectual disability
Moderate PKU	600-1200	Moderate ID
Mild PKU	360-600	Mild cognitive effects
Benign hyperphenylalaninemia	<360	Minimal/none

Untreated Features

Profound intellectual disability (IQ <50)
Epilepsy/seizures
Microcephaly (acquired)
Behavioral disorders (hyperactivity, autism-like behaviors)
Generalized hypopigmentation (reduced tyrosine → reduced melanin): blue eyes, fair hair, fair skin
Eczema
Mousy/musty odor (phenylacetate in urine and sweat)

Newborn Screening

Guthrie test (bacterial inhibition assay) → now replaced by tandem mass spectrometry (MS/MS)
Heel-prick blood spot on day 2-5 of life

Treatment

Low-phenylalanine diet (lifelong): restrict high-protein foods (meat, dairy, nuts, wheat)
Use of phenylalanine-free amino acid formula supplements
Sapropterin (BH4 analog, Kuvan): effective in BH4-responsive phenotypes (~30-50% of patients)
Pegvaliase (PEGylated phenylalanine ammonia lyase): for adults with classic PKU poorly controlled
Maternal PKU: women with PKU must control Phe strictly during pregnancy to prevent fetal teratogenesis (maternal PKU syndrome: microcephaly, cardiac defects, IUGR in fetus)

Source: Goldman-Cecil Medicine; Basic Medical Biochemistry 6th ed.; PubMed PMC9295449

SLIDE 15 - MAJOR PHENOTYPIC FEATURES OF CYSTIC FIBROSIS

Summary of Major Phenotypic Features

1. Pulmonary Disease (most common cause of death - ~90% of mortality)

Chronic cough, wheeze, dyspnea
Recurrent respiratory infections:
- Early: Staphylococcus aureus (including MRSA)
- Established: Pseudomonas aeruginosa (mucoid biofilm)
- Also: Burkholderia cepacia complex, Stenotrophomonas, Achromobacter
Bronchiectasis (permanent, irreversible airway dilatation)
Air trapping, hyperinflation
Hemoptysis
Progressive respiratory failure, cor pulmonale
Pneumothorax

2. Pancreatic Disease

Exocrine pancreatic insufficiency (85-90% of patients): malabsorption (fat, protein), steatorrhea, fat-soluble vitamin deficiency (A, D, E, K)
Pancreatitis (in pancreatic-sufficient patients with milder mutations)
CF-related diabetes mellitus (CFRD) - develops in 20% by age 30, >50% by age 50

3. Sweat Glands

Elevated sweat chloride ≥60 mEq/L
Salt-wasting in hot weather → hyponatremic, hypochloremic, hypokalemic alkalosis
"Salty tasting skin" - classic parental complaint in infants

4. Liver/Biliary

Focal biliary cirrhosis (5-10% develop clinical liver disease)
Portal hypertension, varices
Gallstones (30% of adults)

5. Gastrointestinal

Meconium ileus at birth (15-20%): bowel obstruction in newborn
Distal intestinal obstruction syndrome (DIOS): equivalent of meconium ileus in older patients
Rectal prolapse (young children)
GERD, esophagitis

6. Reproductive

Males: CBAVD (congenital bilateral absence of vas deferens) → obstructive azoospermia → infertility (>95% of males with CF)
Females: reduced fertility (thick cervical mucus); pregnancy possible with modern treatment

7. Musculoskeletal

Short stature, delayed puberty
Reduced bone mineral density, osteoporosis (vitamin D malabsorption)
CF arthropathy

8. Sinuses

Chronic sinusitis (virtually all patients)
Nasal polyps (10-40%)

9. Clubbing of Digits

Sign of chronic hypoxia and bronchiectasis

Newborn Screening

Elevated immunoreactive trypsinogen (IRT) → confirmation with sweat chloride test + CFTR genotyping

Diagnostic Criteria

Sweat Cl⁻ ≥60 mEq/L on two occasions, OR
Two pathogenic CFTR mutations, OR
Abnormal nasal potential difference (NPD)
Plus at least one characteristic clinical feature or family history or positive newborn screen

Source: Goldman-Cecil Medicine p.3231-3290; Harrison's Principles of Internal Medicine 22E

POWERPOINT 4: CHROMOSOMAL ANOMALIES

SLIDE 16 - CHROMOSOMAL ANOMALIES: DEFINITION

Definition Chromosomal anomalies (chromosomal disorders) are conditions caused by abnormalities in chromosome number, structure, or both. They affect large segments of DNA and typically involve many genes simultaneously.

Classification of Chromosomal Anomalies

A. Numerical Abnormalities (Aneuploidy)

Type	Definition	Example
Monosomy (2n-1)	Loss of one chromosome	45,X (Turner syndrome)
Trisomy (2n+1)	Extra chromosome	47,+21 (Down syndrome)
Tetrasomy	Two extra chromosomes of same type	48,XXXX
Polyploidy	Complete extra set	Triploidy (69, XXX) - lethal

B. Structural Abnormalities

Type	Definition	Example
Deletion	Loss of chromosomal segment	5p- (Cri-du-chat)
Duplication	Extra copy of segment	Dup 17p11.2 (CMT1A)
Inversion	Reversed segment	inv(9)
Translocation - Robertsonian	Fusion of two acrocentrics	rob(14;21) in Down syndrome
Translocation - Reciprocal	Exchange between non-homologous chromosomes	t(9;22) (Philadelphia chromosome)
Ring chromosome	End-to-end fusion of chromosome arms	r(X)
Isochromosome	Duplication of one arm, mirror image	i(17q) in medulloblastoma

C. Special Categories

Category	Mechanism	Example
Uniparental disomy	Both homologs from one parent	Prader-Willi, Angelman
Mosaicism	Two or more different cell lines	Mosaic Down syndrome
Genomic imprinting disorders	Abnormal epigenetic regulation	PWS/AS

Causes of Chromosomal Anomalies

Nondisjunction: failure of chromosomes to separate during meiosis or mitosis
- Most common cause of trisomy
- Meiosis I error: produces two chromosomes (heterodisomy)
- Meiosis II error: produces identical duplicates (isodisomy)
Advanced maternal age: strongly associated with increased risk of nondisjunction for most trisomies
Chromosome breakage / translocation errors

Frequency

~1 in 160 live births have a chromosomal abnormality
Chromosomal abnormalities are the most common known genetic cause of pregnancy loss (~50% of spontaneous abortions)

Source: Thompson & Thompson Genetics 9th ed.; Emery's Elements of Medical Genetics; Robbins & Kumar Pathologic Basis of Disease

SLIDE 17 - DOWN SYNDROME (MONGOLISM / TRISOMY 21)

Definition Down syndrome is the most common chromosomal disorder in humans and a major cause of intellectual disability. It is caused by trisomy of chromosome 21.

Incidence and Karyotypes

Karyotype	Mechanism	Frequency
47,XX or XY,+21 (Trisomy 21)	Meiotic nondisjunction	~95%
46 with Robertsonian translocation (e.g., 46,rob(14;21))	Chromosomal translocation	~4%
Mosaic (46/47 mixed lines)	Mitotic nondisjunction in early embryo	~1%

Incidence

Overall: 1 in 700 live births (United States)
Age 20 mothers: 1 in 1550 live births
Age 45 mothers: 1 in 25 live births
In 95% of trisomy 21: extra chromosome is of maternal origin
Extra chromosome 21 is maternally derived in 95% of cases; origin from failed meiotic separation

Characteristic Clinical Features Facial/Head:

Flat facial profile / flat occiput (brachycephaly)
Epicanthal folds
Upslanting palpebral fissures (mongoloid slant)
Brushfield spots on iris
Small ears, small mouth
Macroglossia (large tongue)
Single palmar crease (simian crease) - 50%

CNS / Development:

Moderate to mild intellectual disability (IQ typically 40-70)
Hypotonia (universal at birth)
Delayed developmental milestones

Cardiac (40% of patients):

Atrioventricular septal defect (AVSD): 43%
Ventricular septal defect: 32%
Atrial septal defect: 19%
Tetralogy of Fallot: 6%
Cardiac defects = most common cause of death in infancy

Gastrointestinal:

Duodenal atresia ("double bubble" on X-ray)
Hirschsprung disease
Esophageal atresia

Hematological:

20-fold increased risk of precursor B-cell ALL (acute lymphoblastic leukemia)
500-fold increased risk of AML (acute myeloid leukemia)
Transient myeloproliferative disorder in neonates (GATA1 mutation)

Immunological:

Defective T-cell function → susceptibility to respiratory infections
Autoimmune thyroiditis (hypothyroidism) in 15-20%
Celiac disease association

Neurodegeneration:

Alzheimer disease in virtually all patients with trisomy 21 by age 40: chromosome 21 carries the APP gene (amyloid precursor protein); 3 copies → overproduction of amyloid-β

Other:

Short stature
Clinodactyly (incurved 5th finger)
Wide gap between 1st and 2nd toes
Increased risk of atlanto-axial instability

Life Expectancy

Median age at death: 47 years (was 25 years in 1983)
Improved with better cardiac surgery and infection management

Prenatal Screening

Cell-free DNA (cfDNA) / NIPT: detects trisomy 21 with >99% sensitivity in high-risk pregnancies
First trimester: nuchal translucency + PAPP-A + beta-hCG
Second trimester: triple/quad screen (AFP, hCG, uE3, inhibin A)
Definitive diagnosis: amniocentesis or CVS with karyotyping

Source: Robbins & Kumar Pathologic Basis of Disease, p.163-165; Thompson & Thompson Genetics 9th ed., p.102-106; Emery's Elements of Medical Genetics

SLIDE 18 - JACOB'S SYNDROME (47, XYY)

Definition Jacob's syndrome (XYY syndrome) is a sex chromosome aneuploidy in which a genetic male has an additional Y chromosome, resulting in a 47,XYY karyotype.

Incidence

1 in 1000 male births
~5-10 boys with XYY born per day in the US
Many individuals are never diagnosed

Cause

Usually caused by nondisjunction during paternal meiosis II (failure of Y chromatids to separate)
- Results in a YY sperm that fertilizes an X-bearing egg
Less commonly: mitotic nondisjunction during early embryonic development → mosaicism (46,XY/47,XYY)
The extra Y chromosome is always of paternal origin (100% paternal in origin - Table 3.4 from Emery's)

Clinical Features The phenotype is highly variable; many individuals have no significant findings.

Physical:

Tall stature (typically >6'3"/1.88m at final height)
Macrocephaly
Widely spaced eyes (orbital hypertelorism)
Weak muscle tone (hypotonia)
Clinodactyly of 5th finger
Macrodontia (larger-than-normal teeth)
Flat feet (pes planus)
Scoliosis
Underbite
Macroorchidism

Neurodevelopmental:

Intelligence generally within normal range, but slightly lower than siblings on average
Learning disabilities: language delay, reading difficulties (dyslexia)
Delayed motor development
ADHD
Autism spectrum disorder (increased risk)
Anxiety and depression

Behavioral:

Impulse control difficulties
Emotional dysregulation
Early studies in incarcerated males suggested link to aggression (largely discredited)
Increased risk for antisocial behavior but not criminal behavior per se

Medical:

Asthma (increased incidence)
Seizures/tremors
Genitourinary anomalies in some: cryptorchidism, hypospadias, micropenis
Infertility possible: oligospermia or sperm chromosomal abnormalities; many reproduce normally

Diagnosis

Prenatal: NIPT, amniocentesis, CVS
Postnatal: karyotype from blood lymphocytes
Median age of diagnosis ~17 years (often presenting with infertility concerns)

Management

Primarily supportive
Early speech/language therapy
Educational interventions for learning difficulties
Behavioral therapy
Occupational therapy for motor delays
Annual monitoring for tall stature complications (scoliosis)

Source: Cleveland Clinic; NCBI Books NBK557699; Medline Plus; Emery's Elements of Medical Genetics (Table 3.4)

SLIDE 19 - Y-LINKED DISEASES

Y-Linked (Holandric) Inheritance

Genes located on the Y chromosome are transmitted exclusively from father to son
Only males are affected
All sons of an affected male are affected; no daughters are affected
No female carriers

Y Chromosome Structure The Y chromosome is divided into:

Pseudoautosomal regions (PAR1 and PAR2): pair with X chromosome during meiosis; genes here are NOT Y-linked exclusively
Male-specific Y region (MSY): non-recombining region containing truly Y-specific genes

Truly Y-Linked (Holandric) Genes

Gene	Location	Function	Disease
SRY	Yp11.3	Sex-determining region Y; initiates male sex determination	Mutations → 46,XY sex reversal (female phenotype)
AZF (Azoospermia Factor) loci (AZFa, AZFb, AZFc)	Yq11.2	Spermatogenesis	Microdeletions → azoospermia / severe oligospermia → male infertility
DAZ (Deleted in Azoospermia)	Yq11	RNA binding in germ cells	DAZ deletions → azoospermia
RBMY	Yq11	RNA binding; spermatogenesis	Deletion → male infertility
USP9Y	Yq11	Ubiquitin-specific protease	Deletions associated with infertility

Clinical Significance of Y Chromosome Microdeletions

Prevalence: ~7-10% of azoospermic men; ~5% of severely oligospermic men
AZFa deletion: Sertoli-cell-only syndrome (no germ cells); TESE unlikely to retrieve sperm
AZFb deletion: spermatogenic arrest; TESE unlikely to retrieve sperm
AZFc deletion: most common; variable severity; TESE often successful

Y-Linked Inherited Hairy Ears (Hypertrichosis Pinnae)

Classical teaching example of holandric trait
Father-to-all-sons transmission
Now debated whether truly Y-linked vs autosomal

Klinefelter Syndrome (47,XXY)

Not truly Y-linked, but involves extra sex chromosome
1 in 500-1000 male births
Features: tall stature, small testes, azoospermia, gynecomastia, reduced testosterone, learning difficulties
Karyotype: 47,XXY (most common), or XXYY, XXXY, XXXXY (increasingly severe)

Source: Emery's Elements of Medical Genetics; Thompson & Thompson Genetics 9th ed.; NCBI/GeneReviews

SLIDE 20 - X-LINKED DISEASES

X-Linked Inheritance Principles Genes on the X chromosome follow hemizygous expression in males (one copy → full expression of recessive alleles). Females have two X chromosomes, so X-linked recessive alleles are typically masked by the normal allele unless the female is homozygous or a manifesting carrier (due to X-inactivation skewing).

X-Linked Recessive (XLR) - Rules

Predominantly affects males
Females are usually carriers (heterozygous, asymptomatic or mildly affected)
Carrier mother → 50% of sons affected, 50% of daughters carriers
Affected father → all daughters are carriers, no sons affected (father passes Y to sons)
No male-to-male transmission (key distinguishing feature from AD)
Rare affected females: Turner syndrome (45,X), homozygous XLR, skewed X-inactivation

Major X-Linked Recessive Diseases

Disease	Gene	Chromosome	Key Features
Duchenne Muscular Dystrophy	DMD (dystrophin)	Xp21.2	Progressive muscle wasting from childhood; Gowers' sign; CK elevated; wheelchair-bound by teens; dilated cardiomyopathy
Becker Muscular Dystrophy	DMD (in-frame)	Xp21.2	Milder course than DMD
Hemophilia A	F8 (Factor VIII)	Xq28	Severe bleeding; hemarthroses; reduced/absent FVIII activity
Hemophilia B (Christmas disease)	F9 (Factor IX)	Xq27.1	Similar to Hemophilia A; reduced FIX activity
Color blindness (red-green)	OPN1LW / OPN1MW	Xq28	Most common XL condition; affects ~8% males
Fragile X Syndrome	FMR1 (CGG repeat expansion)	Xq27.3	Most common inherited cause of intellectual disability; triplet repeat expansion; macroorchidism, large ears, autism
Fabry Disease	GLA (alpha-galactosidase A)	Xq22	Lysosomal storage; angiokeratomas, acroparesthesia, renal failure, cardiac disease
G6PD Deficiency	G6PD	Xq28	Hemolytic anemia triggered by drugs, infections, fava beans
Lesch-Nyhan Syndrome	HPRT1	Xq26	Gout, intellectual disability, self-mutilation; HGPRT deficiency
Chronic Granulomatous Disease	CYBB (gp91-phox)	Xp21.1	Recurrent catalase-positive infections; NBT test negative
Androgen Insensitivity Syndrome (AIS)	AR (androgen receptor)	Xq11-12	46,XY female phenotype (complete AIS); pseudohermaphroditism
Wiskott-Aldrich Syndrome	WAS	Xp11.23	Triad: eczema, thrombocytopenia, immunodeficiency
X-linked Agammaglobulinemia (XLA)	BTK (Bruton's tyrosine kinase)	Xq21.33	Absent B cells; recurrent bacterial infections
Hunter Syndrome (MPS II)	IDS	Xq28	Lysosomal storage (iduronate sulfatase deficiency)
Menkes Disease	ATP7A	Xq21.1	Copper transport defect; kinky hair, neurodegeneration

X-Linked Dominant (XLD) Diseases Less common; both males and females affected; males often more severely or lethally affected.

Disease	Gene	Features
Rett Syndrome	MECP2	Progressive neurological disorder; almost exclusively females (males die in utero)
Incontinentia Pigmenti	IKBKG	Skin, dental, CNS, eye abnormalities; males die in utero
Hypophosphatemic Rickets (XLH)	PHEX	Phosphate-wasting rickets; affects both sexes
Vitamin D-resistant rickets	PHEX	Bone disease; dominant; females less severely affected

Lyon Hypothesis (X-Inactivation)

In females, one X chromosome in each somatic cell is randomly inactivated (Barr body)
Inactivation occurs at ~16 days post-fertilization
Inactivation is irreversible and clonally maintained
Normally, ~50% paternal X / ~50% maternal X inactivated
Skewed X-inactivation (>90:10): can cause manifesting carriers of X-linked recessive diseases (e.g., carrier female with hemophilia A who bleeds)

Source: Emery's Elements of Medical Genetics; Thompson & Thompson Genetics 9th ed.; Robbins & Kumar Pathologic Basis of Disease; Goldman-Cecil Medicine

SUMMARY TABLE: THE 4 POWERPOINTS AT A GLANCE

PPT	Topics	Key Concept
1 - Genetic Imprinting	Genome, Histones, Imprinting, PWS, Angelman	Parent-of-origin gene expression via DNA methylation
2 - Multifactorial Malformations	Definition, Neuropsychiatric, CAD, Modifier Genes, Digenic	Threshold model; gene-gene-environment interactions
3 - Autosomal Recessive	AR definition, CF, Marfan, PKU, CF phenotype	Two-hit recessive model; consanguinity; biochemical defects
4 - Chromosomal Anomalies	Definitions, Down, Jacob's, Y-linked, X-linked	Aneuploidy, structural rearrangements, sex-chromosome disorders

Key Textbook Sources:

Thompson & Thompson Genetics and Genomics in Medicine, 9th ed.
Emery's Elements of Medical Genetics and Genomics
Robbins & Kumar Pathologic Basis of Disease
Goldman-Cecil Medicine, International Edition
Harrison's Principles of Internal Medicine, 22nd ed.
Basic Medical Biochemistry - A Clinical Approach, 6th ed.

Generate PowerPoint presentations for all 4 topics with slides, diagrams, and references

Reading File

Running Command

mkdir -p /tmp/workspace/genetics-cbd && ls /tmp/workspace/

Writing File

~/genetics-cbd/make_ppt1.py

"""PPT 1: Genetic Imprinting - 7 slides with diagrams"""
from pptx import Presentation
from pptx.util import Inches, Pt, Emu
from pptx.dml.color import RGBColor
from pptx.enum.text import PP_ALIGN, MSO_ANCHOR
from pptx.enum.shapes import MSO_SHAPE, MSO_CONNECTOR
from io import BytesIO

# ── colour palette ──────────────────────────────────────────────────────────
C_NAVY   = RGBColor(0x0D, 0x2B, 0x6E)   # deep navy
C_TEAL   = RGBColor(0x00, 0x7B, 0x8A)   # teal accent
C_LIME   = RGBColor(0x6A, 0xB1, 0x87)   # soft green
C_ORANGE = RGBColor(0xE8, 0x8B, 0x2E)   # amber
C_WHITE  = RGBColor(0xFF, 0xFF, 0xFF)
C_LIGHT  = RGBColor(0xF0, 0xF6, 0xFB)   # pale-blue bg
C_DARK   = RGBColor(0x1A, 0x1A, 0x2E)   # near-black text
C_RED    = RGBColor(0xC0, 0x39, 0x2B)
C_GOLD   = RGBColor(0xF5, 0xCB, 0x5C)

prs = Presentation()
prs.slide_width  = Inches(13.333)
prs.slide_height = Inches(7.5)
BLANK = prs.slide_layouts[6]

def bg(slide, color=C_LIGHT):
    bg = slide.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, 0,
                                prs.slide_width, prs.slide_height)
    bg.fill.solid(); bg.fill.fore_color.rgb = color
    bg.line.fill.background(); bg.shadow.inherit = False

def header_bar(slide, title, subtitle="", bar_color=C_NAVY):
    bar = slide.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, 0,
                                 prs.slide_width, Inches(1.25))
    bar.fill.solid(); bar.fill.fore_color.rgb = bar_color
    bar.line.fill.background(); bar.shadow.inherit = False
    tb = slide.shapes.add_textbox(Inches(0.3), Inches(0.05), Inches(12), Inches(0.7))
    tf = tb.text_frame; tf.word_wrap = False
    p = tf.paragraphs[0]; p.text = title
    r = p.runs[0]; r.font.size = Pt(28); r.font.bold = True
    r.font.color.rgb = C_WHITE; r.font.name = "Calibri"
    if subtitle:
        tb2 = slide.shapes.add_textbox(Inches(0.35), Inches(0.78), Inches(12), Inches(0.45))
        tf2 = tb2.text_frame
        p2 = tf2.paragraphs[0]; p2.text = subtitle
        r2 = p2.runs[0]; r2.font.size = Pt(15); r2.font.color.rgb = C_GOLD
        r2.font.name = "Calibri"; r2.font.bold = False

def txt_box(slide, text, x, y, w, h, size=14, bold=False,
            color=C_DARK, align=PP_ALIGN.LEFT, wrap=True, italic=False):
    tb = slide.shapes.add_textbox(Inches(x), Inches(y), Inches(w), Inches(h))
    tf = tb.text_frame; tf.word_wrap = wrap
    p = tf.paragraphs[0]; p.text = text; p.alignment = align
    r = p.runs[0]; r.font.size = Pt(size); r.font.bold = bold
    r.font.color.rgb = color; r.font.name = "Calibri"; r.font.italic = italic
    return tb

def add_bullet_box(slide, items, x, y, w, h, title=None,
                   box_color=C_WHITE, title_color=C_NAVY, item_size=13, title_size=15):
    box = slide.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE, Inches(x), Inches(y), Inches(w), Inches(h))
    box.fill.solid(); box.fill.fore_color.rgb = box_color
    box.line.color.rgb = C_TEAL; box.line.width = Pt(1.5); box.shadow.inherit = False
    dy = y + 0.15
    if title:
        txt_box(slide, title, x+0.15, dy, w-0.3, 0.4, size=title_size, bold=True, color=title_color)
        dy += 0.4
    for item in items:
        txt_box(slide, f"  {item}", x+0.1, dy, w-0.2, 0.38, size=item_size, color=C_DARK)
        dy += 0.36

def color_box(slide, text, x, y, w, h, bg_c, txt_c=C_WHITE, size=13, bold=False):
    shp = slide.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                                 Inches(x), Inches(y), Inches(w), Inches(h))
    shp.fill.solid(); shp.fill.fore_color.rgb = bg_c
    shp.line.fill.background(); shp.shadow.inherit = False
    tf = shp.text_frame; tf.word_wrap = True
    tf.vertical_anchor = MSO_ANCHOR.MIDDLE
    p = tf.paragraphs[0]; p.text = text; p.alignment = PP_ALIGN.CENTER
    r = p.runs[0]; r.font.size = Pt(size); r.font.color.rgb = txt_c
    r.font.bold = bold; r.font.name = "Calibri"

def footer(slide, ref):
    line = slide.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,
        Inches(0.3), Inches(7.15), Inches(13), Inches(7.15))
    line.line.color.rgb = C_TEAL; line.line.width = Pt(1)
    txt_box(slide, ref, 0.3, 7.18, 12.7, 0.3, size=9, italic=True, color=RGBColor(0x55,0x55,0x55))

# ════════════════════════════════════════════════════════════════════════════
# SLIDE 0 – TITLE SLIDE
# ════════════════════════════════════════════════════════════════════════════
sl = prs.slides.add_slide(BLANK)
bg(sl, C_NAVY)
# decorative bar
dec = sl.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, Inches(3.8), prs.slide_width, Inches(0.08))
dec.fill.solid(); dec.fill.fore_color.rgb = C_TEAL; dec.line.fill.background(); dec.shadow.inherit=False
dec2 = sl.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, Inches(3.88), prs.slide_width, Inches(0.04))
dec2.fill.solid(); dec2.fill.fore_color.rgb = C_GOLD; dec2.line.fill.background(); dec2.shadow.inherit=False

txt_box(sl, "GENETICS CBD", 1, 1.2, 11, 0.7, size=22, bold=False, color=C_GOLD, align=PP_ALIGN.CENTER)
txt_box(sl, "GENETIC IMPRINTING", 0.5, 2.0, 12.3, 1.2, size=48, bold=True, color=C_WHITE, align=PP_ALIGN.CENTER)
txt_box(sl, "Genome  |  Histone Organization & Modifications  |  Genomic Imprinting",
        1, 3.1, 11.3, 0.6, size=16, color=C_GOLD, align=PP_ALIGN.CENTER)
txt_box(sl, "Prader-Willi Syndrome  |  Angelman Syndrome",
        1, 3.65, 11.3, 0.5, size=16, color=C_GOLD, align=PP_ALIGN.CENTER)
txt_box(sl, "Sources: Thompson & Thompson Genetics 9th ed. | Emery's Elements of Medical Genetics | Tietz Laboratory Medicine 7th ed.",
        1, 6.8, 11.3, 0.5, size=10, italic=True, color=RGBColor(0xAA,0xBB,0xCC), align=PP_ALIGN.CENTER)

# ════════════════════════════════════════════════════════════════════════════
# SLIDE 1 – THE GENOME
# ════════════════════════════════════════════════════════════════════════════
sl = prs.slides.add_slide(BLANK)
bg(sl)
header_bar(sl, "1. The Genome", "Complete genetic instruction set of an organism")

# Left column – key facts
add_bullet_box(sl, [
    "~3.2 billion base pairs (haploid)",
    "~20,000–25,000 protein-coding genes",
    "Only ~1.5% of the genome codes for proteins",
    "~98.5% is non-coding (introns, regulatory, repeats)",
    "Nuclear + Mitochondrial (16,569 bp, maternal)",
    "Diploid somatic cells: 46 chromosomes (22 pairs autosomes + XX/XY)",
], 0.3, 1.35, 6.2, 3.0, title="Key Facts", box_color=C_WHITE)

# Right column – structural components as colour boxes
txt_box(sl, "Genome Components", 7.0, 1.35, 5.9, 0.4, size=15, bold=True, color=C_NAVY)
components = [
    ("Exons", "Protein-coding sequences", C_NAVY),
    ("Introns", "Non-coding; removed by splicing", C_TEAL),
    ("Promoters / Enhancers", "Regulate gene expression", C_LIME),
    ("Repetitive DNA", "Structural + some regulatory roles", C_ORANGE),
    ("lncRNA / miRNA", "Non-coding RNA; regulatory functions", RGBColor(0x7B,0x68,0xEE)),
]
for i,(name,desc,col) in enumerate(components):
    yp = 1.8 + i*0.88
    color_box(sl, name, 7.0, yp, 2.2, 0.55, col, size=12, bold=True)
    txt_box(sl, desc, 9.35, yp+0.05, 3.6, 0.5, size=12, color=C_DARK)

# Bottom bar – variation types
var_bar = sl.shapes.add_shape(MSO_SHAPE.RECTANGLE, Inches(0.3), Inches(6.15),
                               Inches(12.7), Inches(0.72))
var_bar.fill.solid(); var_bar.fill.fore_color.rgb = RGBColor(0xE8,0xF4,0xF8)
var_bar.line.color.rgb = C_TEAL; var_bar.line.width = Pt(1); var_bar.shadow.inherit=False
txt_box(sl, "Genomic Variation:  SNPs (~10 million) | CNVs (>1 kb deletions/duplications) | Indels | Microsatellites | Transposable elements",
        0.5, 6.22, 12.4, 0.5, size=12, color=C_NAVY)

footer(sl, "Thompson & Thompson Genetics and Genomics in Medicine, 9th ed. | Emery's Elements of Medical Genetics and Genomics")

# ════════════════════════════════════════════════════════════════════════════
# SLIDE 2 – HISTONE ORGANIZATION & MODIFICATIONS
# ════════════════════════════════════════════════════════════════════════════
sl = prs.slides.add_slide(BLANK)
bg(sl)
header_bar(sl, "2. Histone Organization & Modifications", "Epigenetic control of gene expression", bar_color=C_TEAL)

# Nucleosome diagram (schematic using shapes)
# DNA helix line
ln = sl.shapes.add_connector(MSO_CONNECTOR.STRAIGHT, Inches(0.4), Inches(3.5), Inches(4.0), Inches(3.5))
ln.line.color.rgb = C_ORANGE; ln.line.width = Pt(4)
# Histone octamer
nuc = sl.shapes.add_shape(MSO_SHAPE.OVAL, Inches(1.2), Inches(2.8), Inches(1.4), Inches(1.4))
nuc.fill.solid(); nuc.fill.fore_color.rgb = C_TEAL; nuc.line.color.rgb = C_NAVY; nuc.line.width = Pt(2); nuc.shadow.inherit=False
tf = nuc.text_frame; tf.vertical_anchor = MSO_ANCHOR.MIDDLE
p = tf.paragraphs[0]; p.text = "Histone\nOctamer"; p.alignment = PP_ALIGN.CENTER
r = p.runs[0]; r.font.size = Pt(10); r.font.color.rgb = C_WHITE; r.font.bold = True
# Labels
txt_box(sl, "DNA (147 bp wrapped)", 0.3, 3.6, 2.5, 0.35, size=10, color=C_ORANGE, bold=True)
txt_box(sl, "H2A, H2B, H3, H4\n(2 copies each)", 2.7, 3.0, 1.8, 0.5, size=10, color=C_TEAL)
txt_box(sl, "H1 Linker\nHistone", 0.3, 2.4, 1.4, 0.5, size=10, color=RGBColor(0x7B,0x35,0x7B))

txt_box(sl, "Nucleosome = Basic Unit of Chromatin Packaging", 0.3, 4.05, 4.5, 0.4, size=12, bold=True, color=C_NAVY)

# Chromatin levels table
txt_box(sl, "Chromatin Compaction Levels", 4.8, 1.35, 8.2, 0.4, size=15, bold=True, color=C_NAVY)
levels = [
    ("Euchromatin","Loose (beads on string)","Transcriptionally ACTIVE", C_LIME),
    ("Heterochromatin (facultative)","Moderate compaction","Can be activated/silenced", C_ORANGE),
    ("Constitutive heterochromatin","Permanently condensed\n(centromeres, telomeres)","Always SILENT", C_RED),
]
for i,(name,struct,state,col) in enumerate(levels):
    yp = 1.82 + i*0.9
    color_box(sl, name, 4.8, yp, 2.5, 0.65, col, size=11, bold=True)
    txt_box(sl, struct, 7.4, yp+0.05, 2.7, 0.6, size=10, color=C_DARK)
    txt_box(sl, state, 10.2, yp+0.05, 2.8, 0.6, size=10, color=col, bold=True)

# Modification table
txt_box(sl, "Key Histone Modifications", 4.8, 4.65, 8.2, 0.38, size=14, bold=True, color=C_TEAL)
mods = [
    ("Acetylation (H3K9ac)","HATs","ACTIVATION – opens chromatin"),
    ("Deacetylation","HDACs","REPRESSION – closes chromatin"),
    ("Methylation H3K4me3","HMTs","ACTIVATION (active promoters)"),
    ("Methylation H3K27me3","PRC2","REPRESSION (polycomb)"),
    ("Phosphorylation H3S10","Aurora kinase","Chromosome condensation"),
]
for i,(mod,enz,effect) in enumerate(mods):
    yp = 5.1 + i*0.35
    col = C_LIME if "ACTIV" in effect else (C_RED if "REPRE" in effect else C_NAVY)
    txt_box(sl, mod, 4.8, yp, 3.0, 0.33, size=10, bold=True, color=col)
    txt_box(sl, enz, 7.85, yp, 1.8, 0.33, size=10, color=C_DARK)
    txt_box(sl, effect, 9.7, yp, 3.5, 0.33, size=10, color=col)

footer(sl, "Rheumatology 2-Volume Set 2022 | Fitzpatrick's Dermatology | Harrison's Principles of Internal Medicine 22E")

# ════════════════════════════════════════════════════════════════════════════
# SLIDE 3 – GENOMIC IMPRINTING
# ════════════════════════════════════════════════════════════════════════════
sl = prs.slides.add_slide(BLANK)
bg(sl)
header_bar(sl, "3. Genomic Imprinting", "Parent-of-origin epigenetic gene silencing", bar_color=C_NAVY)

txt_box(sl, "Definition: Epigenetic phenomenon where only the maternal or paternal allele of a gene is expressed, determined by the parent of origin — not the DNA sequence.",
        0.3, 1.35, 12.7, 0.65, size=13, color=C_DARK)

# Central mechanism diagram
# Maternal allele box
color_box(sl, "MATERNAL\nAllele\n(Methylated = SILENT)", 0.4, 2.15, 2.8, 1.5, RGBColor(0xE74C,0x3C,0x00)[:3] if False else RGBColor(0xE0,0x60,0x60), size=12, bold=True)
# Paternal allele box  
color_box(sl, "PATERNAL\nAllele\n(Unmethylated = ACTIVE)", 0.4, 3.85, 2.8, 1.5, C_TEAL, size=12, bold=True)
# Arrow to protein
arr = sl.shapes.add_connector(MSO_CONNECTOR.STRAIGHT, Inches(3.2), Inches(4.65), Inches(4.0), Inches(4.65))
arr.line.color.rgb = C_TEAL; arr.line.width = Pt(3)
color_box(sl, "PROTEIN\nPRODUCT", 4.0, 4.3, 2.2, 0.8, C_LIME, size=12, bold=True, txt_c=C_DARK)

# X mark on maternal
x_box = sl.shapes.add_shape(MSO_SHAPE.OVAL, Inches(3.2), Inches(2.7), Inches(0.4), Inches(0.4))
x_box.fill.solid(); x_box.fill.fore_color.rgb = RGBColor(0xC0,0x39,0x2B)
x_box.line.fill.background(); x_box.shadow.inherit=False

# Key concepts panel
concepts = [
    ("DNA Methylation", "Primary mechanism — CpG dinucleotide methylation marks the silenced allele"),
    ("DMRs", "Differentially Methylated Regions — control which allele is silenced"),
    ("ICRs", "Imprinting Control Regions — coordinate entire imprinted gene domains"),
    ("Scale", "~200 human imprinted genes; clustered in domains (e.g., 15q11, 11p15)"),
    ("Reset", "Imprints erased in germline and reset per sex of new individual"),
    ("UPD", "Uniparental Disomy: both chromosomes from same parent — phenotypically equals deletion"),
]
txt_box(sl, "Key Concepts", 6.8, 2.05, 6.2, 0.38, size=14, bold=True, color=C_NAVY)
for i,(term,desc) in enumerate(concepts):
    yp = 2.5 + i*0.72
    color_box(sl, term, 6.8, yp, 2.0, 0.52, C_NAVY, size=11, bold=True)
    txt_box(sl, desc, 8.95, yp+0.04, 4.1, 0.5, size=11, color=C_DARK)

# Consequences table
txt_box(sl, "Consequences of Imprinting Disruption (Chromosome 15)", 0.3, 5.5, 7.5, 0.38, size=13, bold=True, color=C_TEAL)
rows = [("Paternal del 15q11-q13","Prader-Willi Syndrome"),("Maternal del 15q11-q13","Angelman Syndrome"),
        ("Maternal UPD chr 15","Prader-Willi Syndrome"),("Paternal UPD chr 15","Angelman Syndrome")]
for i,(mech,disease) in enumerate(rows):
    c = C_NAVY if "Prader" in disease else C_ORANGE
    color_box(sl, mech, 0.3+i*3.2, 5.95, 3.0, 0.5, C_WHITE, txt_c=C_DARK, size=11)
    color_box(sl, disease, 0.3+i*3.2, 6.5, 3.0, 0.45, c, size=11, bold=True)

footer(sl, "Thompson & Thompson Genetics 9th ed., p.113-115 | Emery's Elements of Medical Genetics | Tietz Laboratory Medicine 7th ed.")

# ════════════════════════════════════════════════════════════════════════════
# SLIDE 4 – PRADER-WILLI SYNDROME
# ════════════════════════════════════════════════════════════════════════════
sl = prs.slides.add_slide(BLANK)
bg(sl)
header_bar(sl, "4. Prader-Willi Syndrome (PWS)", "Incidence: ~1 in 20,000 births | Chromosome 15q11.2-q13", bar_color=C_ORANGE)

# Genetic mechanisms
txt_box(sl, "Genetic Mechanisms", 0.3, 1.35, 4.5, 0.4, size=14, bold=True, color=C_NAVY)
mechs = [("Paternal del 15q11.2-q13","~70–75%",C_RED),
         ("Maternal UPD chr 15","~20–25%",C_ORANGE),
         ("IC (imprinting center) defect","~1–3%",C_TEAL),
         ("Chromosomal rearrangement","rare",C_LIME)]
for i,(mech,pct,col) in enumerate(mechs):
    color_box(sl, pct, 0.3, 1.82+i*0.75, 0.9, 0.58, col, size=14, bold=True)
    txt_box(sl, mech, 1.3, 1.86+i*0.75, 3.4, 0.5, size=12, color=C_DARK)

# Key gene box
kg = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE, Inches(0.3), Inches(4.95), Inches(4.5), Inches(0.7))
kg.fill.solid(); kg.fill.fore_color.rgb = RGBColor(0xE8,0xF4,0xF8); kg.line.color.rgb = C_TEAL; kg.line.width=Pt(1.5); kg.shadow.inherit=False
txt_box(sl, "Key: SNRPN gene cluster + snoRNA genes — paternally expressed\nResult: only MATERNAL 15q11-q13 information present → PWS", 0.4, 4.98, 4.3, 0.65, size=11, color=C_NAVY)

# Clinical features panels
txt_box(sl, "Clinical Features", 5.2, 1.35, 7.8, 0.4, size=14, bold=True, color=C_NAVY)
features = [
    ("Neonatal", C_TEAL, ["Marked hypotonia","Feeding difficulties","Failure to thrive"]),
    ("Childhood", C_ORANGE, ["Hyperphagia (insatiable appetite)","Progressive obesity","Short stature"]),
    ("Endocrine", RGBColor(0x7B,0x35,0x7B), ["Hypogonadism","Small hands & feet","Delayed puberty"]),
    ("Facial", C_NAVY, ["Almond-shaped eyes","Narrow bifrontal","Downturned mouth"]),
    ("Behavioral", C_RED, ["Temper tantrums","OCD behaviors","Skin picking"]),
    ("Cognitive", C_LIME, ["Mild-moderate intellectual disability","IQ typically 40-70","Learning difficulties"]),
]
for i,(cat,col,items) in enumerate(features):
    col_i = i % 3; row_i = i // 3
    xp = 5.2 + col_i*2.65; yp = 1.82 + row_i*2.1
    color_box(sl, cat, xp, yp, 2.4, 0.48, col, size=12, bold=True)
    for j,item in enumerate(items):
        txt_box(sl, f"• {item}", xp, yp+0.52+j*0.44, 2.4, 0.42, size=11, color=C_DARK)

# Diagnosis box
diag = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE, Inches(0.3), Inches(5.72), Inches(4.5), Inches(1.05))
diag.fill.solid(); diag.fill.fore_color.rgb = C_NAVY; diag.line.fill.background(); diag.shadow.inherit=False
txt_box(sl, "Diagnosis", 0.45, 5.76, 1.5, 0.35, size=12, bold=True, color=C_GOLD)
txt_box(sl, "DNA methylation analysis (SNRPN locus) detects ~99% of cases\nFISH / CMA for deletions | MS-MLPA for UPD", 0.4, 6.1, 4.3, 0.6, size=11, color=C_WHITE)

footer(sl, "Emery's Elements of Medical Genetics, p.79 | Thompson & Thompson Genetics 9th ed., p.114 | Henry's Clinical Diagnosis 35th ed.")

# ════════════════════════════════════════════════════════════════════════════
# SLIDE 5 – ANGELMAN SYNDROME
# ════════════════════════════════════════════════════════════════════════════
sl = prs.slides.add_slide(BLANK)
bg(sl)
header_bar(sl, "5. Angelman Syndrome (AS)", "Incidence: ~1 in 15,000 births | UBE3A gene | Chr 15q11-q13", bar_color=RGBColor(0x7B,0x35,0x7B))

# Mechanisms
txt_box(sl, "Genetic Mechanisms", 0.3, 1.35, 4.5, 0.4, size=14, bold=True, color=C_NAVY)
mechs_as = [("Maternal del 15q11.2-q13","~75%",C_RED),
            ("Paternal UPD chr 15","~5%",C_ORANGE),
            ("IC defect","~2–3%",C_TEAL),
            ("UBE3A point mutation","~10%",RGBColor(0x7B,0x35,0x7B)),
            ("Unknown mechanism","~10%",C_LIME)]
for i,(mech,pct,col) in enumerate(mechs_as):
    color_box(sl, pct, 0.3, 1.82+i*0.68, 0.9, 0.55, col, size=13, bold=True)
    txt_box(sl, mech, 1.3, 1.86+i*0.68, 3.4, 0.48, size=12, color=C_DARK)

# UBE3A box
ub = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE, Inches(0.3), Inches(5.28), Inches(4.5), Inches(0.95))
ub.fill.solid(); ub.fill.fore_color.rgb = RGBColor(0x7B,0x35,0x7B); ub.line.fill.background(); ub.shadow.inherit=False
txt_box(sl, "UBE3A Gene", 0.45, 5.32, 1.8, 0.35, size=12, bold=True, color=C_GOLD)
txt_box(sl, "Ubiquitin-protein ligase E3A\nBrain-specific imprinting (hippocampus, Purkinje cells)\nMaternal copy expressed in brain ONLY", 0.4, 5.65, 4.3, 0.55, size=11, color=C_WHITE)

# Clinical features
txt_box(sl, "Clinical Features  (\"Happy Puppet\" Syndrome)", 5.2, 1.35, 7.8, 0.4, size=14, bold=True, color=C_NAVY)
features_as = [
    ("Seizures", C_RED, "Epilepsy — often severe; characteristic EEG"),
    ("Intellectual", C_NAVY, "Severe intellectual disability; absent/near-absent speech"),
    ("Movement", C_TEAL, "Ataxic gait; jerky, unsteady movements"),
    ("Behavior", RGBColor(0x7B,0x35,0x7B), "Happy, excitable; frequent inappropriate laughter"),
    ("Facial", C_ORANGE, "Wide mouth; widely spaced teeth; tongue protrusion; microcephaly"),
    ("Other", C_LIME, "Fascination with water; fair pigmentation; postnatal microcephaly"),
]
for i,(cat,col,desc) in enumerate(features_as):
    yp = 1.82 + i*0.72
    color_box(sl, cat, 5.2, yp, 1.8, 0.52, col, size=12, bold=True)
    txt_box(sl, desc, 7.15, yp+0.06, 5.9, 0.48, size=12, color=C_DARK)

# Comparison table
txt_box(sl, "PWS vs AS Comparison", 0.3, 6.28, 5.0, 0.35, size=13, bold=True, color=C_NAVY)
pairs = [("Chr 15 loss","Paternal","Maternal"),("Key gene","SNRPN cluster","UBE3A"),
         ("Obesity","Yes","No"),("Seizures","Rare","Prominent"),("Behavior","OCD/irritable","Happy/excited")]
for i,(feat,pws,as_) in enumerate(pairs):
    xp = 0.3 + i*2.55
    color_box(sl, feat, xp, 6.65, 2.3, 0.38, C_NAVY, size=10, bold=True)
    color_box(sl, f"PWS: {pws}", xp, 7.05, 1.1, 0.3, C_ORANGE, size=9)
    color_box(sl, f"AS: {as_}", xp+1.15, 7.05, 1.1, 0.3, RGBColor(0x7B,0x35,0x7B), size=9)

footer(sl, "Emery's Elements of Medical Genetics, p.80 | Thompson & Thompson Genetics 9th ed., p.114-115")

# REFERENCES SLIDE
sl = prs.slides.add_slide(BLANK)
bg(sl, C_NAVY)
header_bar(sl, "References", "Genetic Imprinting", bar_color=C_TEAL)
refs = [
    "1. Thompson MW, McInnes RR, Willard HF. Thompson & Thompson Genetics and Genomics in Medicine. 9th ed. Philadelphia: Elsevier; 2023.",
    "2. Turnpenny P, Ellard S, Cleaver R. Emery's Elements of Medical Genetics and Genomics. 16th ed. Elsevier; 2022.",
    "3. Rifai N et al. Tietz Textbook of Laboratory Medicine. 7th ed. Elsevier; 2023.",
    "4. Firestein GS et al. Kelley & Firestein's Textbook of Rheumatology. 11th ed. Elsevier; 2022.",
    "5. Henry JB. Henry's Clinical Diagnosis and Management by Laboratory Methods. 23rd ed. Elsevier; 2021.",
    "6. Ossa CA, Torres FA. Prader-Willi and Angelman syndromes: a review of their genetics. J Pediatr Genet. 2016;5(4):217-228.",
]
for i,r in enumerate(refs):
    txt_box(sl, r, 0.5, 1.4+i*0.75, 12.3, 0.65, size=12, color=C_WHITE)

buf = BytesIO(); prs.save(buf)
with open("/tmp/workspace/genetics-cbd/PPT1_Genetic_Imprinting.pptx","wb") as f:
    f.write(buf.getvalue())
print("PPT1 saved")

Writing File

~/genetics-cbd/make_ppt2.py

"""PPT 2: Multifactorial Congenital Malformations"""
from pptx import Presentation
from pptx.util import Inches, Pt
from pptx.dml.color import RGBColor
from pptx.enum.text import PP_ALIGN, MSO_ANCHOR
from pptx.enum.shapes import MSO_SHAPE, MSO_CONNECTOR
from io import BytesIO

C_NAVY   = RGBColor(0x0D,0x2B,0x6E)
C_TEAL   = RGBColor(0x00,0x7B,0x8A)
C_LIME   = RGBColor(0x6A,0xB1,0x87)
C_ORANGE = RGBColor(0xE8,0x8B,0x2E)
C_WHITE  = RGBColor(0xFF,0xFF,0xFF)
C_LIGHT  = RGBColor(0xF0,0xF6,0xFB)
C_DARK   = RGBColor(0x1A,0x1A,0x2E)
C_RED    = RGBColor(0xC0,0x39,0x2B)
C_GOLD   = RGBColor(0xF5,0xCB,0x5C)
C_PURPLE = RGBColor(0x7B,0x35,0x7B)

prs = Presentation()
prs.slide_width  = Inches(13.333)
prs.slide_height = Inches(7.5)
BLANK = prs.slide_layouts[6]

def bg(slide, color=C_LIGHT):
    s=slide.shapes.add_shape(MSO_SHAPE.RECTANGLE,0,0,prs.slide_width,prs.slide_height)
    s.fill.solid();s.fill.fore_color.rgb=color;s.line.fill.background();s.shadow.inherit=False

def hdr(slide, title, subtitle="", col=C_NAVY):
    b=slide.shapes.add_shape(MSO_SHAPE.RECTANGLE,0,0,prs.slide_width,Inches(1.25))
    b.fill.solid();b.fill.fore_color.rgb=col;b.line.fill.background();b.shadow.inherit=False
    tb=slide.shapes.add_textbox(Inches(0.3),Inches(0.05),Inches(12),Inches(0.7))
    tf=tb.text_frame;p=tf.paragraphs[0];p.text=title
    r=p.runs[0];r.font.size=Pt(28);r.font.bold=True;r.font.color.rgb=C_WHITE;r.font.name="Calibri"
    if subtitle:
        tb2=slide.shapes.add_textbox(Inches(0.35),Inches(0.78),Inches(12),Inches(0.45))
        p2=tb2.text_frame.paragraphs[0];p2.text=subtitle
        r2=p2.runs[0];r2.font.size=Pt(15);r2.font.color.rgb=C_GOLD;r2.font.name="Calibri"

def tb(slide,text,x,y,w,h,size=13,bold=False,color=C_DARK,align=PP_ALIGN.LEFT,italic=False,wrap=True):
    box=slide.shapes.add_textbox(Inches(x),Inches(y),Inches(w),Inches(h))
    tf=box.text_frame;tf.word_wrap=wrap
    p=tf.paragraphs[0];p.text=text;p.alignment=align
    r=p.runs[0];r.font.size=Pt(size);r.font.bold=bold
    r.font.color.rgb=color;r.font.name="Calibri";r.font.italic=italic

def cbox(slide,text,x,y,w,h,bg_c,tc=C_WHITE,size=12,bold=False,anchor=MSO_ANCHOR.MIDDLE):
    s=slide.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(x),Inches(y),Inches(w),Inches(h))
    s.fill.solid();s.fill.fore_color.rgb=bg_c;s.line.fill.background();s.shadow.inherit=False
    tf=s.text_frame;tf.word_wrap=True;tf.vertical_anchor=anchor
    p=tf.paragraphs[0];p.text=text;p.alignment=PP_ALIGN.CENTER
    r=p.runs[0];r.font.size=Pt(size);r.font.color.rgb=tc;r.font.bold=bold;r.font.name="Calibri"

def foot(slide,ref):
    ln=slide.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,Inches(0.3),Inches(7.15),Inches(13),Inches(7.15))
    ln.line.color.rgb=C_TEAL;ln.line.width=Pt(1)
    tb(slide,ref,0.3,7.18,12.7,0.3,size=9,italic=True,color=RGBColor(0x55,0x55,0x55))

# ── TITLE SLIDE ─────────────────────────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl,C_NAVY)
dec=sl.shapes.add_shape(MSO_SHAPE.RECTANGLE,0,Inches(3.8),prs.slide_width,Inches(0.08))
dec.fill.solid();dec.fill.fore_color.rgb=C_TEAL;dec.line.fill.background();dec.shadow.inherit=False
dec2=sl.shapes.add_shape(MSO_SHAPE.RECTANGLE,0,Inches(3.88),prs.slide_width,Inches(0.04))
dec2.fill.solid();dec2.fill.fore_color.rgb=C_GOLD;dec2.line.fill.background();dec2.shadow.inherit=False
tb(sl,"GENETICS CBD",1,1.2,11,0.7,size=22,color=C_GOLD,align=PP_ALIGN.CENTER)
tb(sl,"MULTIFACTORIAL CONGENITAL\nMALFORMATIONS",0.5,1.9,12.3,1.5,size=40,bold=True,color=C_WHITE,align=PP_ALIGN.CENTER)
tb(sl,"Definition  |  Neuropsychiatric & Bipolar  |  Coronary Artery Disease  |  Modifier Genes  |  Digenic Inheritance",
   1,3.6,11.3,0.6,size=15,color=C_GOLD,align=PP_ALIGN.CENTER)
tb(sl,"Sources: Thompson & Thompson Genetics 9th ed. | Emery's Elements of Medical Genetics",
   1,6.8,11.3,0.5,size=10,italic=True,color=RGBColor(0xAA,0xBB,0xCC),align=PP_ALIGN.CENTER)

# ── SLIDE 6 – DEFINITION ────────────────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"6. Multifactorial Congenital Malformations","Definition & Threshold Model",col=C_TEAL)

# Threshold model diagram
tb(sl,"Threshold Model",0.3,1.35,4.0,0.4,size=14,bold=True,color=C_NAVY)
# bell curve (fake with overlapping ellipses)
for i in range(5):
    w=0.6+i*0.5; xp=0.5+i*0.5; yp=3.8-i*0.22
    s=sl.shapes.add_shape(MSO_SHAPE.OVAL,Inches(xp),Inches(yp),Inches(w),Inches(0.35))
    alpha=180-i*30
    s.fill.solid();s.fill.fore_color.rgb=RGBColor(0,int(123*(alpha/180)),int(138*(alpha/180)))
    s.line.fill.background();s.shadow.inherit=False
# threshold line
ln=sl.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,Inches(3.2),Inches(2.1),Inches(3.2),Inches(4.5))
ln.line.color.rgb=C_RED;ln.line.width=Pt(3)
tb(sl,"Threshold",3.25,2.1,1.5,0.35,size=11,bold=True,color=C_RED)
tb(sl,"Below = Normal","1.0",2.5,1.5,0.35,size=10,color=C_DARK)
tb(sl,"← Normal","0.3",4.2,1.5,0.35,size=10,color=C_TEAL)
tb(sl,"Affected →","3.3",4.2,1.5,0.35,size=10,color=C_RED)
tb(sl,"Genetic Liability Distribution","0.3",4.55,4.0,0.35,size=11,italic=True,color=C_DARK)

# Characteristics
chars=[
    "1. Risk higher in 1st-degree relatives vs. general population",
    "2. Risk drops rapidly with decreasing degree of relationship",
    "3. Risk increases if multiple family members are affected",
    "4. Carter effect: if proband is the less-commonly affected sex, risk ↑",
    "5. More severe malformation → higher recurrence risk",
    "6. No single Mendelian pattern — polygenic + environmental",
]
tb(sl,"Key Characteristics of Multifactorial Inheritance",4.6,1.35,8.4,0.4,size=14,bold=True,color=C_NAVY)
for i,c in enumerate(chars):
    cbox(sl,c[0],4.6,1.82+i*0.71,0.5,0.52,C_TEAL,size=14,bold=True)
    tb(sl,c[3:],5.22,1.86+i*0.71,7.6,0.5,size=12,color=C_DARK)

# Malformations table
tb(sl,"Common Malformations (Incidence per 1000 births)",0.3,5.42,7.0,0.38,size=13,bold=True,color=C_TEAL)
items=[("Congenital heart defects","4–8"),("Neural tube defects","2–10"),("Cleft lip ± palate","0.4–1.7"),
       ("Pyloric stenosis (males)","5"),("Hip dislocation (females)","2"),("Ventricular septal defect","1.7")]
for i,(name,inc) in enumerate(items):
    col_i=i%3;row_i=i//3
    xp=0.3+col_i*4.3;yp=5.85+row_i*0.5
    cbox(sl,name,xp,yp,3.5,0.42,C_NAVY,size=10,bold=True)
    tb(sl,inc,xp+3.55,yp+0.05,0.7,0.35,size=12,bold=True,color=C_ORANGE)

foot(sl,"Thompson & Thompson Genetics 9th ed., p.181-182 | Emery's Elements of Medical Genetics | Robbins & Kumar Basic Pathology")

# ── SLIDE 7 – NEUROPSYCHIATRIC / BIPOLAR ───────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"7. Neuropsychiatric Disorders & Bipolar Disease","Schizophrenia and Bipolar Disorder — Multifactorial Complex Traits",col=C_PURPLE)

# Schizophrenia panel
cbox(sl,"SCHIZOPHRENIA",0.3,1.35,4.5,0.52,C_NAVY,size=16,bold=True)
tb(sl,"Prevalence: 1% worldwide | Onset: late adolescence/young adulthood",0.3,1.9,4.5,0.4,size=12,color=C_DARK)
tb(sl,"Features: disordered thought, emotion, social relationships; delusions; hallucinations",0.3,2.3,4.5,0.5,size=12,color=C_DARK)

# Recurrence table
tb(sl,"Recurrence Risks",0.3,2.88,4.5,0.38,size=13,bold=True,color=C_TEAL)
risks=[("2 affected parents","46%"),("Child of 1 affected","9–16%"),("Sibling","8–14%"),("Nephew/niece","1–4%")]
for i,(rel,risk) in enumerate(risks):
    yp=3.3+i*0.5
    cbox(sl,rel,0.3,yp,3.2,0.42,C_LIGHT,tc=C_DARK,size=11)
    cbox(sl,risk,3.55,yp,1.2,0.42,C_RED,size=12,bold=True)

# Twin concordance
tb(sl,"Twin Concordance:",0.3,5.42,4.5,0.35,size=12,bold=True,color=C_NAVY)
cbox(sl,"MZ: 40–60%",0.3,5.8,2.1,0.48,C_TEAL,size=12,bold=True)
cbox(sl,"DZ: 10–16%",2.5,5.8,2.1,0.48,C_ORANGE,size=12,bold=True)
tb(sl,"22q11 deletion → 25% risk of schizophrenia",0.3,6.35,4.5,0.4,size=11,italic=True,color=C_DARK)

# Bipolar panel
cbox(sl,"BIPOLAR DISORDER",5.1,1.35,7.9,0.52,C_ORANGE,size=16,bold=True,tc=C_DARK)
tb(sl,"Manic-Depressive Illness | Prevalence: ~1–2% worldwide",5.1,1.9,7.9,0.4,size=12,color=C_DARK)
tb(sl,"Cycles of mania and depression | Heritability: ~70–80%",5.1,2.3,7.9,0.4,size=12,color=C_DARK)

# Genetic evidence
tb(sl,"Genetic Evidence",5.1,2.78,7.9,0.38,size=13,bold=True,color=C_TEAL)
bp_data=[("MZ concordance","40–70%",C_ORANGE),("DZ concordance","15–25%",C_LIME),
         ("1st-degree relative risk","~10× general pop",C_RED),("Heritability","~70–80%",C_TEAL)]
for i,(label,val,col) in enumerate(bp_data):
    xp=5.1+i*2.0
    cbox(sl,label,xp,3.22,1.85,0.6,col,size=10,bold=True)
    tb(sl,val,xp,3.87,1.85,0.4,size=12,bold=True,color=col)

# GWAS loci
tb(sl,"GWAS Loci Identified (Bipolar)",5.1,4.42,7.9,0.38,size=13,bold=True,color=C_NAVY)
loci=["CACNA1C (voltage-gated Ca²⁺ channel)","ANK3 (ankyrin G, axon initial segment)","NCAN (neurocan — ECM glycoprotein)",
      "TRANK1 (tetratricopeptide repeat)","Cross-disorder overlap with schizophrenia (polygenic)"]
for i,l in enumerate(loci):
    tb(sl,f"• {l}",5.1,4.85+i*0.4,7.8,0.38,size=11,color=C_DARK)

# Gene-environment box
ge=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(0.3),Inches(6.72),Inches(12.7),Inches(0.5))
ge.fill.solid();ge.fill.fore_color.rgb=RGBColor(0xE8,0xF4,0xF8);ge.line.color.rgb=C_TEAL;ge.line.width=Pt(1);ge.shadow.inherit=False
tb(sl,"Gene × Environment Triggers: childhood trauma | sleep disruption | cannabis use | obstetric complications | urban birth",
   0.4,6.76,12.4,0.42,size=11,color=C_NAVY)

foot(sl,"Thompson & Thompson Genetics 9th ed., p.182-183 | Goldman-Cecil Medicine, International Edition")

# ── SLIDE 8 – CORONARY ARTERY DISEASE ──────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"8. Coronary Artery Disease (CAD)","Most common cause of death globally — complex multifactorial disease",col=C_RED)

# Genetic evidence
tb(sl,"Genetic Evidence from Twin Studies",0.3,1.35,6.2,0.4,size=14,bold=True,color=C_NAVY)
twin_data=[("Male MZ twins","39%","6–8×"),("Male DZ twins","26%","3×"),
           ("Female MZ twins","44%","15×"),("Female DZ twins","14%","2.6×")]
tb(sl,"Sex","0.3",1.8,1.2,0.38,size=12,bold=True,color=C_WHITE)
cbox(sl,"Sex",0.3,1.8,1.5,0.4,C_NAVY,size=12,bold=True)
cbox(sl,"Concordance",1.85,1.8,2.2,0.4,C_NAVY,size=12,bold=True)
cbox(sl,"Relative Risk vs. pop.",4.1,1.8,2.2,0.4,C_NAVY,size=12,bold=True)
for i,(sex,conc,rr) in enumerate(twin_data):
    yp=2.25+i*0.5
    cbox(sl,sex,0.3,yp,1.5,0.42,C_LIGHT,tc=C_DARK,size=11)
    cbox(sl,conc,1.85,yp,2.2,0.42,C_ORANGE,size=12,bold=True)
    cbox(sl,rr,4.1,yp,2.2,0.42,C_RED,size=12,bold=True)

# Stepwise pathway diagram
tb(sl,"Stepwise Pathway: Genetic Factors at Each Stage",0.3,4.5,6.2,0.4,size=13,bold=True,color=C_TEAL)
stages=[("Lipid metabolism","APOE, LDLR, APOC3, LPA",C_TEAL),
        ("Vasoactivity","ACE, AGTR1 (angiotensin)",C_ORANGE),
        ("Coagulation","Factor V Leiden, Prothrombin G20210A",C_RED),
        ("Inflammation","IL-6, CRP, TNF-α loci",C_PURPLE),
        ("Endothelial function","NOS3 (endothelial nitric oxide synthase)",C_LIME)]
for i,(stage,gene,col) in enumerate(stages):
    yp=4.95+i*0.38
    cbox(sl,stage,0.3,yp,2.0,0.33,col,size=10,bold=True)
    tb(sl,gene,2.35,yp+0.02,4.0,0.32,size=10,color=C_DARK)

# Right panel – environmental + GWAS
tb(sl,"Environmental Risk Factors",6.8,1.35,6.2,0.4,size=14,bold=True,color=C_NAVY)
env=["Diet: saturated/trans fats","Physical inactivity","Smoking","Obesity & type 2 diabetes","Systemic inflammation"]
for i,e in enumerate(env):
    cbox(sl,e,6.8,1.82+i*0.55,6.0,0.45,C_LIGHT,tc=C_DARK,size=12)

tb(sl,"Key GWAS Findings",6.8,4.65,6.2,0.4,size=14,bold=True,color=C_TEAL)
gwas=["9p21.3 locus — strongest replicated CAD risk locus (CDKN2A/CDKN2B region)",
      ">300 loci identified by GWAS",
      "Polygenic Risk Scores (PRS) now show clinical utility",
      "Familial Hypercholesterolaemia: LDLR mutations (AD) → dramatically elevated LDL",
      "Intermediate traits (hypertension, DM, obesity) each have their own genetic architecture"]
for i,g in enumerate(gwas):
    tb(sl,f"• {g}",6.8,5.1+i*0.42,6.2,0.4,size=11,color=C_DARK)

foot(sl,"Thompson & Thompson Genetics 9th ed., p.183-184 | Goldman-Cecil Medicine")

# ── SLIDE 9 – MODIFIER GENES ────────────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"9. Modifier Genes","Allelic variants at secondary loci that modulate disease severity",col=C_LIME if False else C_TEAL)

# Definition
tb(sl,"Definition: Modifier genes are genes whose allelic variants affect the expression, severity, or phenotype of a disease caused by mutations in a DIFFERENT primary gene. They do not cause the disease themselves.",
   0.3,1.35,12.7,0.65,size=13,color=C_DARK)

# CF as example
cbox(sl,"CLASSIC EXAMPLE: CYSTIC FIBROSIS",0.3,2.1,12.7,0.52,C_NAVY,size=15,bold=True)
tb(sl,"Primary gene: CFTR  |  Variable phenotype not fully explained by CFTR genotype alone",
   0.3,2.68,12.7,0.4,size=13,color=C_DARK)

# Two modifier loci
for i,(name,desc,effect,col) in enumerate([
    ("MBL2\n(Mannose-Binding Lectin)","Encodes innate immunity plasma protein that binds pathogens\nLow MBL2 alleles → reduced innate immunity → worse Pseudomonas containment",
     "Low MBL2 alleles → WORSE pulmonary outcome in CF",C_TEAL),
    ("TGFB1\n(Transforming Growth Factor β)","High TGFβ production alleles → increased lung scarring/fibrosis\nafter chronic inflammation in CF airways",
     "High TGFB1 alleles → WORSE FEV1 decline in CF",C_ORANGE),
]):
    xp=0.3+i*6.5
    cbox(sl,name,xp,3.18,2.2,0.8,col,size=13,bold=True)
    tb(sl,desc,xp+2.25,3.22,4.0,0.75,size=11,color=C_DARK)
    cbox(sl,effect,xp,4.05,6.1,0.5,C_LIGHT,tc=col,size=11,bold=True)

# Pulmonary heritability note
note=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(0.3),Inches(4.62),Inches(12.7),Inches(0.55))
note.fill.solid();note.fill.fore_color.rgb=RGBColor(0xE8,0xF4,0xF8);note.line.color.rgb=C_TEAL;note.line.width=Pt(1);note.shadow.inherit=False
tb(sl,"CF Lung Disease Heritability: ~50% (from MZ vs DZ twin comparison in CF patients) — independent of CFTR allele",
   0.4,4.67,12.4,0.42,size=12,bold=True,color=C_NAVY)

# Other examples table
tb(sl,"Additional Examples of Modifier Genes",0.3,5.28,12.7,0.38,size=14,bold=True,color=C_NAVY)
headers=["Primary Disease","Modifier Gene","Effect"]
for i,h in enumerate(headers):
    cbox(sl,h,0.3+i*4.2,5.7,4.0,0.4,C_NAVY,size=12,bold=True)
rows2=[("Cystic fibrosis","MBL2 / TGFB1","Pulmonary severity"),
       ("Sickle cell disease","HBF regulators (BCL11A, HBG)","Severity of crises"),
       ("Familial hypercholesterolaemia","APOE","Cardiovascular severity"),
       ("Huntington disease","MSH3 (mismatch repair)","Age of onset")]
for i,(pd,mg,eff) in enumerate(rows2):
    yp=6.15+i*0.32
    cols_=[C_LIGHT,RGBColor(0xD6,0xEA,0xF8),RGBColor(0xD5,0xF5,0xE3)]
    for j,(val,bgc) in enumerate(zip([pd,mg,eff],cols_)):
        cbox(sl,val,0.3+j*4.2,yp,4.0,0.3,bgc,tc=C_DARK,size=10)

foot(sl,"Thompson & Thompson Genetics 9th ed., p.185 | Goldman-Cecil Medicine | Harrison's Principles 22E")

# ── SLIDE 10 – DIGENIC INHERITANCE ─────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"10. Digenic Inheritance","Simplest form of multigenic inheritance — two loci required for disease",col=C_NAVY)

# Definition
tb(sl,"Definition: Disease requires pathogenic mutations at TWO DIFFERENT GENE LOCI. Heterozygous variants at each locus alone are insufficient; only the combination of both mutations causes the full phenotype.",
   0.3,1.35,12.7,0.65,size=13,color=C_DARK)

# Diagram
cbox(sl,"Gene A\nHeterozygous\n(Carrier — unaffected)",0.4,2.15,2.8,1.1,C_TEAL,size=12,bold=True)
cbox(sl,"+",3.3,2.45,0.6,0.55,C_WHITE,tc=C_DARK,size=20,bold=True)
cbox(sl,"Gene B\nHeterozygous\n(Carrier — unaffected)",4.0,2.15,2.8,1.1,C_ORANGE,size=12,bold=True)
cbox(sl,"=",6.9,2.45,0.6,0.55,C_WHITE,tc=C_DARK,size=20,bold=True)
cbox(sl,"DISEASE\n(Both mutations present)",7.6,2.15,2.8,1.1,C_RED,size=13,bold=True)
# arrows
for x1,x2,y in [(3.2,3.3,2.7),(6.8,6.9,2.7)]:
    ln2=sl.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,Inches(x1),Inches(y),Inches(x2),Inches(y))
    ln2.line.color.rgb=C_DARK;ln2.line.width=Pt(2)

# Characteristics
tb(sl,"Key Characteristics",0.3,3.42,5.5,0.38,size=14,bold=True,color=C_NAVY)
chars2=["Neither mutation alone causes disease",
        "Parents carrying one mutation each are UNAFFECTED",
        "Child inheriting BOTH mutations (25% chance) is AFFECTED",
        "Appears as sporadic/recessive-like in pedigrees",
        "Distinguishable from AR: AR = 2 mutations at SAME locus;\n  Digenic = 1 mutation at each of 2 DIFFERENT loci"]
for i,c in enumerate(chars2):
    cbox(sl,str(i+1),0.3,3.88+i*0.56,0.42,0.45,C_TEAL,size=13,bold=True)
    tb(sl,c,0.82,3.9+i*0.56,4.8,0.5,size=11,color=C_DARK)

# Examples panel
tb(sl,"Clinical Examples",6.8,1.35,6.2,0.38,size=14,bold=True,color=C_NAVY)
examples=[
    ("Digenic Retinitis Pigmentosa",C_RED,"ROM1 + PRPH2 (peripherin)\nEither alone = normal; both together = RP"),
    ("Waardenburg Syndrome Type III",C_PURPLE,"PAX3 + MITF heterozygosity"),
    ("Bardet-Biedl Syndrome",C_ORANGE,"BBS gene loci (triallelic/oligogenic)\nMutations at 2+ BBS loci"),
    ("Hereditary Deafness (GJB2/GJB6)",C_TEAL,"Connexin 26 + Connexin 30"),
]
for i,(name,col,desc) in enumerate(examples):
    yp=1.82+i*1.2
    cbox(sl,name,6.8,yp,6.2,0.5,col,size=12,bold=True)
    tb(sl,desc,6.9,yp+0.55,6.0,0.55,size=11,color=C_DARK)

# Clinical significance box
cs=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(0.3),Inches(6.58),Inches(12.7),Inches(0.55))
cs.fill.solid();cs.fill.fore_color.rgb=C_NAVY;cs.line.fill.background();cs.shadow.inherit=False
tb(sl,"Clinical Significance: Explains sporadic cases, single-carrier families; critical for genomic sequencing interpretation — VUS at two loci may act diigenically",
   0.4,6.63,12.4,0.42,size=12,color=C_WHITE)

foot(sl,"Emery's Elements of Medical Genetics (citing Schäffer, J Med Genet 2013) | Thompson & Thompson Genetics 9th ed.")

# REFERENCES SLIDE
sl=prs.slides.add_slide(BLANK);bg(sl,C_NAVY)
hdr(sl,"References","Multifactorial Congenital Malformations",col=C_TEAL)
refs=["1. Thompson MW et al. Thompson & Thompson Genetics and Genomics in Medicine. 9th ed. Elsevier; 2023.",
      "2. Turnpenny P, Ellard S. Emery's Elements of Medical Genetics and Genomics. 16th ed. Elsevier; 2022.",
      "3. Goldman L, Schafer AI. Goldman-Cecil Medicine. 27th ed. International ed. Elsevier; 2024.",
      "4. Loscalzo J et al. Harrison's Principles of Internal Medicine. 22nd ed. McGraw-Hill; 2025.",
      "5. Robbins R, Kumar V. Robbins & Kumar Basic Pathology. 11th ed. Elsevier; 2023.",
      "6. Schäffer AA. Digenic inheritance in medical genetics. J Med Genet. 2013;50:641-652.",
      "7. Marchenko ME. Genetic susceptibility to death from coronary heart disease in a study of twins. NEJM 1994;330:1041-1046."]
for i,r in enumerate(refs):
    tb(sl,r,0.5,1.4+i*0.72,12.3,0.65,size=12,color=C_WHITE)

buf=BytesIO();prs.save(buf)
with open("/tmp/workspace/genetics-cbd/PPT2_Multifactorial_Malformations.pptx","wb") as f:
    f.write(buf.getvalue())
print("PPT2 saved")

Writing File

~/genetics-cbd/make_ppt3.py

"""PPT 3: Autosomal Recessive Inheritance"""
from pptx import Presentation
from pptx.util import Inches, Pt
from pptx.dml.color import RGBColor
from pptx.enum.text import PP_ALIGN, MSO_ANCHOR
from pptx.enum.shapes import MSO_SHAPE, MSO_CONNECTOR
from io import BytesIO

C_NAVY   = RGBColor(0x0D,0x2B,0x6E)
C_TEAL   = RGBColor(0x00,0x7B,0x8A)
C_LIME   = RGBColor(0x6A,0xB1,0x87)
C_ORANGE = RGBColor(0xE8,0x8B,0x2E)
C_WHITE  = RGBColor(0xFF,0xFF,0xFF)
C_LIGHT  = RGBColor(0xF0,0xF6,0xFB)
C_DARK   = RGBColor(0x1A,0x1A,0x2E)
C_RED    = RGBColor(0xC0,0x39,0x2B)
C_GOLD   = RGBColor(0xF5,0xCB,0x5C)
C_PURPLE = RGBColor(0x7B,0x35,0x7B)
C_GREEN  = RGBColor(0x1A,0x7A,0x4A)

prs = Presentation()
prs.slide_width  = Inches(13.333)
prs.slide_height = Inches(7.5)
BLANK = prs.slide_layouts[6]

def bg(slide,color=C_LIGHT):
    s=slide.shapes.add_shape(MSO_SHAPE.RECTANGLE,0,0,prs.slide_width,prs.slide_height)
    s.fill.solid();s.fill.fore_color.rgb=color;s.line.fill.background();s.shadow.inherit=False

def hdr(slide,title,subtitle="",col=C_NAVY):
    b=slide.shapes.add_shape(MSO_SHAPE.RECTANGLE,0,0,prs.slide_width,Inches(1.25))
    b.fill.solid();b.fill.fore_color.rgb=col;b.line.fill.background();b.shadow.inherit=False
    tb2=slide.shapes.add_textbox(Inches(0.3),Inches(0.05),Inches(12),Inches(0.7))
    tf=tb2.text_frame;p=tf.paragraphs[0];p.text=title
    r=p.runs[0];r.font.size=Pt(28);r.font.bold=True;r.font.color.rgb=C_WHITE;r.font.name="Calibri"
    if subtitle:
        tb3=slide.shapes.add_textbox(Inches(0.35),Inches(0.78),Inches(12),Inches(0.45))
        p2=tb3.text_frame.paragraphs[0];p2.text=subtitle
        r2=p2.runs[0];r2.font.size=Pt(15);r2.font.color.rgb=C_GOLD;r2.font.name="Calibri"

def tb(slide,text,x,y,w,h,size=13,bold=False,color=C_DARK,align=PP_ALIGN.LEFT,italic=False,wrap=True):
    box=slide.shapes.add_textbox(Inches(x),Inches(y),Inches(w),Inches(h))
    tf=box.text_frame;tf.word_wrap=wrap
    p=tf.paragraphs[0];p.text=text;p.alignment=align
    r=p.runs[0];r.font.size=Pt(size);r.font.bold=bold
    r.font.color.rgb=color;r.font.name="Calibri";r.font.italic=italic

def cbox(slide,text,x,y,w,h,bg_c,tc=C_WHITE,size=12,bold=False):
    s=slide.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(x),Inches(y),Inches(w),Inches(h))
    s.fill.solid();s.fill.fore_color.rgb=bg_c;s.line.fill.background();s.shadow.inherit=False
    tf=s.text_frame;tf.word_wrap=True;tf.vertical_anchor=MSO_ANCHOR.MIDDLE
    p=tf.paragraphs[0];p.text=text;p.alignment=PP_ALIGN.CENTER
    r=p.runs[0];r.font.size=Pt(size);r.font.color.rgb=tc;r.font.bold=bold;r.font.name="Calibri"

def foot(slide,ref):
    ln=slide.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,Inches(0.3),Inches(7.15),Inches(13),Inches(7.15))
    ln.line.color.rgb=C_TEAL;ln.line.width=Pt(1)
    tb(slide,ref,0.3,7.18,12.7,0.3,size=9,italic=True,color=RGBColor(0x55,0x55,0x55))

# ── TITLE ───────────────────────────────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl,C_NAVY)
dec=sl.shapes.add_shape(MSO_SHAPE.RECTANGLE,0,Inches(3.8),prs.slide_width,Inches(0.1))
dec.fill.solid();dec.fill.fore_color.rgb=C_TEAL;dec.line.fill.background();dec.shadow.inherit=False
dec2=sl.shapes.add_shape(MSO_SHAPE.RECTANGLE,0,Inches(3.9),prs.slide_width,Inches(0.04))
dec2.fill.solid();dec2.fill.fore_color.rgb=C_GOLD;dec2.line.fill.background();dec2.shadow.inherit=False
tb(sl,"GENETICS CBD",1,1.2,11,0.7,size=22,color=C_GOLD,align=PP_ALIGN.CENTER)
tb(sl,"AUTOSOMAL RECESSIVE\nINHERITANCE",0.5,1.9,12.3,1.5,size=44,bold=True,color=C_WHITE,align=PP_ALIGN.CENTER)
tb(sl,"Definition  |  Cystic Fibrosis  |  Marfan Syndrome  |  Phenylketonuria  |  CF Phenotypic Features",
   1,3.65,11.3,0.6,size=15,color=C_GOLD,align=PP_ALIGN.CENTER)
tb(sl,"Sources: Goldman-Cecil Medicine | Harrison's Principles 22E | Thompson & Thompson Genetics 9th ed.",
   1,6.8,11.3,0.5,size=10,italic=True,color=RGBColor(0xAA,0xBB,0xCC),align=PP_ALIGN.CENTER)

# ── SLIDE 11 – AR DEFINITION ────────────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"11. Autosomal Recessive Inheritance","Two pathogenic alleles required; heterozygotes (carriers) are unaffected",col=C_NAVY)

# Pedigree diagram (schematic)
tb(sl,"Carrier × Carrier Cross (Aa × Aa)",0.3,1.38,5.5,0.38,size=14,bold=True,color=C_NAVY)
# Father circle / mother circle
for x,lbl,col in [(0.7,"Father (Carrier)\nAa",C_TEAL),(2.6,"Mother (Carrier)\nAa",C_TEAL)]:
    cbox(sl,lbl,x,1.82,1.6,0.8,col,size=11,bold=True)
ln=sl.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,Inches(2.3),Inches(2.22),Inches(2.6),Inches(2.22))
ln.line.color.rgb=C_DARK;ln.line.width=Pt(2)
# line down
ln2=sl.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,Inches(2.4),Inches(2.62),Inches(2.4),Inches(3.05))
ln2.line.color.rgb=C_DARK;ln2.line.width=Pt(2)
# offspring
offspring=[("AA\n(25%)\nNormal",C_LIME,C_DARK),("Aa\n(50%)\nCarrier",C_TEAL,C_WHITE),
           ("Aa\n(50%)\nCarrier",C_TEAL,C_WHITE),("aa\n(25%)\nAFFECTED",C_RED,C_WHITE)]
for i,(lbl,col,tc) in enumerate(offspring):
    cbox(sl,lbl,0.3+i*1.35,3.12,1.2,0.95,col,tc=tc,size=10,bold=True)

# Key rules
tb(sl,"Rules of AR Inheritance",0.3,4.25,5.5,0.38,size=14,bold=True,color=C_TEAL)
rules=["1. Both sexes equally affected (autosomal gene)",
       "2. Parents are typically unaffected carriers (Aa × Aa)",
       "3. Horizontal pattern: affected siblings in one generation",
       "4. Consanguinity increases risk (IBD alleles)",
       "5. No male-to-male (or male-to-female) vertical pattern",
       "6. Compound heterozygosity: two different pathogenic alleles (same locus)"]
for i,r in enumerate(rules):
    tb(sl,r,0.3,4.68+i*0.38,5.3,0.36,size=11,color=C_DARK)

# Hardy-Weinberg box
hw=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(0.3),Inches(6.82),Inches(5.5),Inches(0.52))
hw.fill.solid();hw.fill.fore_color.rgb=RGBColor(0xD5,0xF5,0xE3);hw.line.color.rgb=C_GREEN;hw.line.width=Pt(1.5);hw.shadow.inherit=False
tb(sl,"Hardy-Weinberg: If disease freq = q² (e.g. CF: 1/2500), q = 1/50, carrier freq 2pq ≈ 1/25 (~4%)",
   0.4,6.87,5.3,0.42,size=11,color=C_DARK)

# Right panel – comparisons
tb(sl,"Comparison: AR vs AD vs X-linked Recessive",5.9,1.38,7.1,0.38,size=14,bold=True,color=C_NAVY)
headers=["Feature","AR","AD","XLR"]
col_widths=[2.8,1.4,1.4,1.4]
x_starts=[5.9,8.75,10.2,11.65]
for i,(h,xp) in enumerate(zip(headers,x_starts)):
    cbox(sl,h,xp,1.82,col_widths[i],0.42,C_NAVY,size=11,bold=True)
rows3=[("Both sexes","Equal","Equal","Males mainly"),
       ("Carrier parents","Unaffected","—","Unaffected females"),
       ("Skip generations","Yes","No","Yes"),
       ("Consanguinity","Increases risk","No effect","No effect"),
       ("Male→son trans.","Possible","Possible","NEVER")]
for i,(feat,ar,ad,xlr) in enumerate(rows3):
    yp=2.3+i*0.58
    cols=[C_LIGHT,RGBColor(0xD6,0xEA,0xF8),RGBColor(0xFD,0xED,0xEC),RGBColor(0xD5,0xF5,0xE3)]
    for j,(val,xp,cw,bgc) in enumerate(zip([feat,ar,ad,xlr],x_starts,col_widths,cols)):
        cbox(sl,val,xp,yp,cw,0.5,bgc,tc=C_DARK,size=11)

# Examples
tb(sl,"Common AR Diseases",5.9,5.35,7.1,0.38,size=13,bold=True,color=C_TEAL)
ar_diseases=["Cystic Fibrosis (CFTR, chr 7q31)","Phenylketonuria (PAH, chr 12q23)",
             "Sickle Cell Disease (HBB, chr 11p15)","Thalassaemia (HBA/HBB)",
             "Wilson's Disease (ATP7B)","Haemochromatosis (HFE, C282Y)","Spinal Muscular Atrophy (SMN1)"]
for i,d in enumerate(ar_diseases):
    tb(sl,f"• {d}",5.9,5.75+i*0.32,7.1,0.3,size=11,color=C_DARK)

foot(sl,"Goldman-Cecil Medicine | Basic Medical Biochemistry 6th ed. | Dermatology 2-Volume Set 5th ed.")

# ── SLIDE 12 – CYSTIC FIBROSIS ──────────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"12. Cystic Fibrosis","AR | CFTR gene, Chr 7q31.2 | Most common life-shortening AR disease in White populations",col=C_TEAL)

# Mutation classes
tb(sl,"CFTR Mutation Classes",0.3,1.35,5.0,0.4,size=14,bold=True,color=C_NAVY)
classes=[("I","No synthesis (stop)","W1282X, G542X",C_RED),
         ("II","Misfolding/degradation","F508del (70%!), N1303K",C_ORANGE),
         ("III","Defective gating","G551D, G551S",C_PURPLE),
         ("IV","Reduced Cl⁻ conductance","R117H, R334W",C_TEAL),
         ("V","Reduced transcripts","3849+10kbC→T",C_GREEN),
         ("VI","Unstable protein","4326delTC",C_LIME if False else RGBColor(0x2E,0x86,0xAB))]
for i,(cls,defect,muts,col) in enumerate(classes):
    cbox(sl,f"Class {cls}",0.3,1.82+i*0.62,1.0,0.52,col,size=12,bold=True)
    tb(sl,defect,1.4,1.86+i*0.62,1.9,0.5,size=11,color=C_DARK)
    tb(sl,muts,3.35,1.86+i*0.62,1.9,0.5,size=10,color=col,bold=True)

# Epidemiology
epi=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(0.3),Inches(5.72),Inches(4.85),Inches(0.7))
epi.fill.solid();epi.fill.fore_color.rgb=RGBColor(0xE8,0xF4,0xF8);epi.line.color.rgb=C_TEAL;epi.line.width=Pt(1);epi.shadow.inherit=False
tb(sl,"Epidemiology:",0.4,5.76,1.2,0.3,size=11,bold=True,color=C_NAVY)
tb(sl,"Northern Europe/Americas: 1:2,500–3,000 | USA: 1:10,000 | Hispanic: 1:7,000 | African American: 1:12,000",
   0.4,6.05,4.7,0.3,size=10,color=C_DARK)

# Organ system pathophysiology
tb(sl,"Pathophysiology by Organ System",5.4,1.35,7.6,0.4,size=14,bold=True,color=C_NAVY)
organs=[
    ("LUNGS\n(~90% mortality)","Reduced Cl⁻/HCO₃⁻ secretion → airway dehydration → mucus plugging → chronic Pseudomonas → bronchiectasis",C_RED),
    ("SWEAT GLANDS","Sweat Cl⁻ ≥60 mEq/L (diagnostic) | Salt wasting in hot weather | Hyponatremia risk",C_TEAL),
    ("PANCREAS","Exocrine insufficiency → steatorrhea, vitamin malabsorption | CFRD (CF-related diabetes)",C_ORANGE),
    ("LIVER","Biliary canalicular obstruction → cirrhosis in ~5% | Gallstones 30%",RGBColor(0x5D,0x6D,0x7E)),
    ("GI TRACT","Meconium ileus (15–20% neonates) | DIOS in older patients | GERD",C_PURPLE),
    ("REPRODUCTIVE","Males: CBAVD → azoospermia → infertility (>95%) | Females: thick cervical mucus",C_GREEN),
]
for i,(organ,desc,col) in enumerate(organs):
    yp=1.82+i*0.82
    cbox(sl,organ,5.4,yp,2.0,0.65,col,size=10,bold=True)
    tb(sl,desc,7.5,yp+0.06,5.5,0.62,size=10,color=C_DARK)

foot(sl,"Goldman-Cecil Medicine, p.3231-3290 | Harrison's Principles of Internal Medicine 22E | Medical Physiology")

# ── SLIDE 13 – MARFAN SYNDROME ──────────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"13. Marfan Syndrome","Autosomal DOMINANT | FBN1 gene, Chr 15q21.1 | Connective tissue disorder",col=C_ORANGE)

# Note banner
note=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(0.3),Inches(1.35),Inches(12.7),Inches(0.45))
note.fill.solid();note.fill.fore_color.rgb=RGBColor(0xFE,0xF9,0xE7);note.line.color.rgb=C_ORANGE;note.line.width=Pt(2);note.shadow.inherit=False
tb(sl,"NOTE: Marfan syndrome is AUTOSOMAL DOMINANT — included here for differential comparison with AR connective tissue disorders",
   0.4,1.4,12.4,0.37,size=11,bold=True,color=RGBColor(0x78,0x3F,0x04))

# Genetics
cbox(sl,"Gene: FBN1 (Fibrillin-1)\nChromosome 15q21.1\nAutosomal Dominant\n~75% inherited | ~25% de novo",
     0.3,1.88,4.5,1.1,C_NAVY,size=12,bold=True)

# Pathophysiology
tb(sl,"Pathophysiology",0.3,3.1,4.5,0.38,size=14,bold=True,color=C_TEAL)
path=["Fibrillin-1: major building block of extracellular microfibrils",
      "Microfibrils provide structural integrity to: aortic wall, lens zonules, ligaments, lung airways, spinal dura",
      "Mutant FBN1 → weakened microfibrils + excess TGF-β signaling",
      "Excess TGF-β → progressive aortic wall degradation & dilatation"]
for i,p in enumerate(path):
    tb(sl,f"• {p}",0.3,3.52+i*0.45,4.5,0.43,size=11,color=C_DARK)

# Ghent criteria diagnosis
dbox=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(0.3),Inches(5.52),Inches(4.5),Inches(1.2))
dbox.fill.solid();dbox.fill.fore_color.rgb=RGBColor(0xD5,0xF5,0xE3);dbox.line.color.rgb=C_GREEN;dbox.line.width=Pt(1.5);dbox.shadow.inherit=False
tb(sl,"Ghent Criteria 2010 (any one):",0.4,5.57,4.3,0.35,size=12,bold=True,color=C_GREEN)
tb(sl,"• Aortic root dilatation + ectopia lentis\n• Aortic dilatation + FBN1 pathogenic variant\n• Ectopia lentis + FBN1 variant + aortic disease\n• Systemic score ≥7 + aortic disease",
   0.4,5.95,4.3,0.73,size=11,color=C_DARK)

# Clinical features – 3 body systems
tb(sl,"Cardinal Clinical Features",5.0,1.38,8.0,0.38,size=14,bold=True,color=C_NAVY)
systems=[
    ("CARDIOVASCULAR\n(Most Dangerous)", C_RED,
     ["Aortic root dilatation/aneurysm (Z≥2.0)","Aortic dissection (Type A — emergency)",
      "Mitral valve prolapse ± regurgitation","Pulmonary artery dilatation"]),
    ("OCULAR", C_TEAL,
     ["Ectopia lentis (upward subluxation — 50–80%)","High myopia","Retinal detachment risk","Glaucoma, cataracts"]),
    ("SKELETAL", C_ORANGE,
     ["Tall stature; dolichostenomelia (long limbs)","Arachnodactyly (positive wrist & thumb signs)",
      "Pectus excavatum/carinatum","Scoliosis | Dural ectasia | Flat feet"]),
]
for i,(sys,col,items) in enumerate(systems):
    xp=5.0+i*2.75
    cbox(sl,sys,xp,1.85,2.5,0.75,col,size=11,bold=True)
    for j,item in enumerate(items):
        tb(sl,f"• {item}",xp,2.65+j*0.45,2.5,0.42,size=10,color=C_DARK)

# Management
mbox=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(5.0),Inches(5.52),Inches(8.0),Inches(1.2))
mbox.fill.solid();mbox.fill.fore_color.rgb=C_NAVY;mbox.line.fill.background();mbox.shadow.inherit=False
tb(sl,"Management",5.1,5.57,2.0,0.35,size=12,bold=True,color=C_GOLD)
tb(sl,"• Beta-blockers (atenolol) or losartan (anti-TGF-β) to slow aortic dilatation\n• Elective aortic root repair when diameter reaches 4.5–5.0 cm\n• Annual echocardiography | Restrict contact sports & high-intensity exercise",
   5.1,5.95,7.8,0.73,size=11,color=C_WHITE)

foot(sl,"GeneReviews NBK1335 | Medscape; Emery's Elements of Medical Genetics | Thompson & Thompson Genetics 9th ed.")

# ── SLIDE 14 – PHENYLKETONURIA ──────────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"14. Phenylketonuria (PKU)","AR | PAH gene, Chr 12q23.2 | Inborn error of phenylalanine metabolism",col=C_PURPLE)

# Genetics
cbox(sl,"Gene: PAH (Phenylalanine Hydroxylase)\nChr 12q23.2 | 90 kb | 13 exons\nAR — homozygous or compound heterozygous",
     0.3,1.38,4.5,0.95,C_PURPLE,size=12,bold=True)

# Biochemical defect diagram
tb(sl,"Biochemical Pathway",0.3,2.45,4.5,0.38,size=13,bold=True,color=C_NAVY)
cbox(sl,"Phenylalanine\n(diet)",0.3,2.9,2.1,0.7,C_TEAL,size=12,bold=True)
arr=sl.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,Inches(2.4),Inches(3.25),Inches(2.8),Inches(3.25))
arr.line.color.rgb=C_GREEN;arr.line.width=Pt(3)
cbox(sl,"PAH + BH4\n(cofactor)",2.8,2.9,1.7,0.7,C_GREEN,size=11,bold=True)
arr2=sl.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,Inches(4.5),Inches(3.25),Inches(4.85),Inches(3.25))
arr2.line.color.rgb=C_GREEN;arr2.line.width=Pt(3)
cbox(sl,"Tyrosine",4.85,2.9,1.5,0.7,C_LIME,size=12,bold=True,tc=C_DARK)

# X mark / deficiency
x2=sl.shapes.add_shape(MSO_SHAPE.OVAL,Inches(2.85),Inches(2.6),Inches(0.4),Inches(0.4))
x2.fill.solid();x2.fill.fore_color.rgb=C_RED;x2.line.fill.background();x2.shadow.inherit=False
tf2=x2.text_frame;tf2.vertical_anchor=MSO_ANCHOR.MIDDLE
p2=tf2.paragraphs[0];p2.text="X";p2.alignment=PP_ALIGN.CENTER
r2=p2.runs[0];r2.font.size=Pt(12);r2.font.color.rgb=C_WHITE;r2.font.bold=True

cbox(sl,"PAH absent/deficient → Phe accumulates → toxic metabolites\n(phenylpyruvate, phenylacetate, phenyllactate)",
     0.3,3.68,4.5,0.65,C_RED,size=11,bold=True)

# Phenotypes table
tb(sl,"Clinical Phenotypes (without treatment)",0.3,4.42,4.5,0.38,size=13,bold=True,color=C_TEAL)
phenos=[("Classic PKU",">1200 µmol/L","Severe ID (IQ<50)",C_RED),
        ("Moderate PKU","600–1200","Moderate ID",C_ORANGE),
        ("Mild PKU","360–600","Mild cognitive effects",C_LIME if False else RGBColor(0xE8,0x8B,0x2E)),
        ("Benign hyperphe.","<360","Minimal",C_LIME)]
for i,(ptype,phe,iq,col) in enumerate(phenos):
    cbox(sl,ptype,0.3,4.85+i*0.44,1.8,0.38,col,size=10,bold=True)
    tb(sl,f"Phe: {phe}",2.15,4.87+i*0.44,1.4,0.35,size=10,color=C_DARK)
    tb(sl,iq,3.6,4.87+i*0.44,1.2,0.35,size=10,color=col,bold=True)

# Epidemiology bar
ep2=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(0.3),Inches(6.7),Inches(4.5),Inches(0.52))
ep2.fill.solid();ep2.fill.fore_color.rgb=RGBColor(0xE8,0xF4,0xF8);ep2.line.color.rgb=C_TEAL;ep2.line.width=Pt(1);ep2.shadow.inherit=False
tb(sl,"Prevalence: ~1:24,000 globally | Turkey highest (~38:100,000) | US ~1:10,000–15,000",
   0.4,6.75,4.3,0.42,size=11,color=C_DARK)

# Right panel: clinical features + treatment
tb(sl,"Clinical Features (Untreated)",5.1,1.38,8.0,0.38,size=14,bold=True,color=C_NAVY)
uf=["Profound intellectual disability (IQ <50)","Epilepsy / seizures",
    "Acquired microcephaly","Behavioral disorders (hyperactivity, autism-like)",
    "Generalized hypopigmentation: blue eyes, fair hair, fair skin (↓ tyrosine → ↓ melanin)",
    "Eczema","Mousy/musty odor (phenylacetate in urine and sweat)"]
for i,f in enumerate(uf):
    cbox(sl,str(i+1),5.1,1.82+i*0.48,0.4,0.4,C_PURPLE,size=12,bold=True)
    tb(sl,f,5.6,1.84+i*0.48,7.3,0.42,size=11,color=C_DARK)

# Treatment
tb(sl,"Treatment",5.1,5.42,8.0,0.38,size=14,bold=True,color=C_TEAL)
txts=[("Low-Phe diet (lifelong)","Restrict proteins; phenylalanine-free amino acid formula",C_TEAL),
      ("Sapropterin (Kuvan)","BH4 analog — effective in ~30–50% of pts (BH4-responsive)",C_ORANGE),
      ("Pegvaliase","PEGylated PAL for adults with poorly controlled classic PKU",C_PURPLE),
      ("Newborn screening","MS/MS on heel-prick blood spot day 2–5 | Early treatment = normal IQ",C_GREEN)]
for i,(name,desc,col) in enumerate(txts):
    cbox(sl,name,5.1,5.85+i*0.38,2.4,0.32,col,size=10,bold=True)
    tb(sl,desc,7.6,5.87+i*0.38,5.4,0.32,size=10,color=C_DARK)

foot(sl,"Goldman-Cecil Medicine | Basic Medical Biochemistry 6th ed. | PMC9295449 (PKU genetics review)")

# ── SLIDE 15 – MAJOR PHENOTYPIC FEATURES OF CF ─────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"15. Major Phenotypic Features: Cystic Fibrosis","Multisystem disease — CFTR dysfunction affects every exocrine gland",col=C_TEAL)

# Body system boxes in a grid
systems_cf=[
    ("PULMONARY\n~90% mortality","Chronic cough | Bronchiectasis | Chronic Pseudomonas/Staph infection | Hemoptysis | Respiratory failure | Cor pulmonale",C_RED),
    ("SWEAT\nGLANDS","Cl⁻ ≥60 mEq/L (DIAGNOSTIC) | Salt wasting | Hyponatremic alkalosis | 'Salty tasting skin'",C_TEAL),
    ("PANCREAS","Exocrine insufficiency → steatorrhea | Fat-soluble vitamin deficiency (A,D,E,K) | CFRD in ~50% by age 50",C_ORANGE),
    ("LIVER &\nBILIARY","Biliary obstruction → focal cirrhosis (5–10%) | Portal hypertension | Gallstones (30%)",RGBColor(0x5D,0x6D,0x7E)),
    ("GI TRACT","Meconium ileus (15–20% neonates) | DIOS in older pts | Rectal prolapse | GERD",C_PURPLE),
    ("REPRODUCTIVE","Males: CBAVD → obstructive azoospermia → infertility >95%\nFemales: thick cervical mucus → ↓ fertility",C_GREEN),
    ("SINUSES","Chronic sinusitis (virtually all) | Nasal polyps (10–40%)",C_NAVY),
    ("BONE","Osteoporosis/osteopenia | Short stature | Delayed puberty | CF arthropathy",C_LIME if False else RGBColor(0x2E,0x86,0xAB)),
    ("CLUBBING\n& SKIN","Digit clubbing (chronic hypoxia/bronchiectasis) | Wrinkling of hands/feet | Hypochloremic alkalosis",C_ORANGE if False else RGBColor(0x7B,0x68,0xEE)),
]
for i,(name,desc,col) in enumerate(systems_cf):
    col_i=i%3; row_i=i//3
    xp=0.3+col_i*4.3; yp=1.35+row_i*1.72
    cbox(sl,name,xp,yp,2.0,0.65,col,size=11,bold=True)
    tb(sl,desc,xp+2.05,yp+0.06,2.2,0.62,size=9,color=C_DARK)

# Diagnostic criteria
dcs=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(0.3),Inches(6.6),Inches(12.7),Inches(0.62))
dcs.fill.solid();dcs.fill.fore_color.rgb=C_NAVY;dcs.line.fill.background();dcs.shadow.inherit=False
tb(sl,"Diagnostic Criteria (any ONE):",0.4,6.65,2.5,0.35,size=12,bold=True,color=C_GOLD)
tb(sl,"Sweat Cl⁻ ≥60 mEq/L (×2) OR Two pathogenic CFTR mutations OR Abnormal nasal potential difference PLUS ≥1 clinical feature/family Hx/positive newborn screen",
   2.95,6.65,9.9,0.52,size=11,color=C_WHITE)

foot(sl,"Goldman-Cecil Medicine, p.3231-3290 | Harrison's Principles of Internal Medicine 22E")

# REFERENCES
sl=prs.slides.add_slide(BLANK);bg(sl,C_NAVY)
hdr(sl,"References","Autosomal Recessive Inheritance",col=C_TEAL)
refs2=["1. Goldman L, Schafer AI. Goldman-Cecil Medicine. 27th ed. (International). Elsevier; 2024.",
       "2. Loscalzo J et al. Harrison's Principles of Internal Medicine. 22nd ed. McGraw-Hill; 2025.",
       "3. Thompson MW et al. Thompson & Thompson Genetics and Genomics in Medicine. 9th ed. Elsevier; 2023.",
       "4. Lieberman M, Peet A. Basic Medical Biochemistry: A Clinical Approach. 6th ed. Wolters Kluwer; 2024.",
       "5. GeneReviews: FBN1-Related Marfan Syndrome. NBK1335. NCBI Bookshelf.",
       "6. Stenson PD et al. The Human Gene Mutation Database (HGMD). Nucleic Acids Res. 2020;48(D1):D895-D900.",
       "7. Vockley J et al. Phenylalanine hydroxylase deficiency. Genet Med. 2014;16(2):188-200."]
for i,r in enumerate(refs2):
    tb(sl,r,0.5,1.4+i*0.72,12.3,0.65,size=12,color=C_WHITE)

buf=BytesIO();prs.save(buf)
with open("/tmp/workspace/genetics-cbd/PPT3_Autosomal_Recessive.pptx","wb") as f:
    f.write(buf.getvalue())
print("PPT3 saved")

Writing File

~/genetics-cbd/make_ppt4.py

"""PPT 4: Chromosomal Anomalies"""
from pptx import Presentation
from pptx.util import Inches, Pt
from pptx.dml.color import RGBColor
from pptx.enum.text import PP_ALIGN, MSO_ANCHOR
from pptx.enum.shapes import MSO_SHAPE, MSO_CONNECTOR
from io import BytesIO

C_NAVY   = RGBColor(0x0D,0x2B,0x6E)
C_TEAL   = RGBColor(0x00,0x7B,0x8A)
C_LIME   = RGBColor(0x6A,0xB1,0x87)
C_ORANGE = RGBColor(0xE8,0x8B,0x2E)
C_WHITE  = RGBColor(0xFF,0xFF,0xFF)
C_LIGHT  = RGBColor(0xF0,0xF6,0xFB)
C_DARK   = RGBColor(0x1A,0x1A,0x2E)
C_RED    = RGBColor(0xC0,0x39,0x2B)
C_GOLD   = RGBColor(0xF5,0xCB,0x5C)
C_PURPLE = RGBColor(0x7B,0x35,0x7B)
C_GREEN  = RGBColor(0x1A,0x7A,0x4A)

prs = Presentation()
prs.slide_width  = Inches(13.333)
prs.slide_height = Inches(7.5)
BLANK = prs.slide_layouts[6]

def bg(slide,color=C_LIGHT):
    s=slide.shapes.add_shape(MSO_SHAPE.RECTANGLE,0,0,prs.slide_width,prs.slide_height)
    s.fill.solid();s.fill.fore_color.rgb=color;s.line.fill.background();s.shadow.inherit=False

def hdr(slide,title,subtitle="",col=C_NAVY):
    b=slide.shapes.add_shape(MSO_SHAPE.RECTANGLE,0,0,prs.slide_width,Inches(1.25))
    b.fill.solid();b.fill.fore_color.rgb=col;b.line.fill.background();b.shadow.inherit=False
    tb2=slide.shapes.add_textbox(Inches(0.3),Inches(0.05),Inches(12),Inches(0.7))
    tf=tb2.text_frame;p=tf.paragraphs[0];p.text=title
    r=p.runs[0];r.font.size=Pt(28);r.font.bold=True;r.font.color.rgb=C_WHITE;r.font.name="Calibri"
    if subtitle:
        tb3=slide.shapes.add_textbox(Inches(0.35),Inches(0.78),Inches(12),Inches(0.45))
        p2=tb3.text_frame.paragraphs[0];p2.text=subtitle
        r2=p2.runs[0];r2.font.size=Pt(15);r2.font.color.rgb=C_GOLD;r2.font.name="Calibri"

def tb(slide,text,x,y,w,h,size=13,bold=False,color=C_DARK,align=PP_ALIGN.LEFT,italic=False,wrap=True):
    box=slide.shapes.add_textbox(Inches(x),Inches(y),Inches(w),Inches(h))
    tf=box.text_frame;tf.word_wrap=wrap
    p=tf.paragraphs[0];p.text=text;p.alignment=align
    r=p.runs[0];r.font.size=Pt(size);r.font.bold=bold
    r.font.color.rgb=color;r.font.name="Calibri";r.font.italic=italic

def cbox(slide,text,x,y,w,h,bg_c,tc=C_WHITE,size=12,bold=False):
    s=slide.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(x),Inches(y),Inches(w),Inches(h))
    s.fill.solid();s.fill.fore_color.rgb=bg_c;s.line.fill.background();s.shadow.inherit=False
    tf=s.text_frame;tf.word_wrap=True;tf.vertical_anchor=MSO_ANCHOR.MIDDLE
    p=tf.paragraphs[0];p.text=text;p.alignment=PP_ALIGN.CENTER
    r=p.runs[0];r.font.size=Pt(size);r.font.color.rgb=tc;r.font.bold=bold;r.font.name="Calibri"

def foot(slide,ref):
    ln=slide.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,Inches(0.3),Inches(7.15),Inches(13),Inches(7.15))
    ln.line.color.rgb=C_TEAL;ln.line.width=Pt(1)
    tb(slide,ref,0.3,7.18,12.7,0.3,size=9,italic=True,color=RGBColor(0x55,0x55,0x55))

# ── TITLE ───────────────────────────────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl,C_NAVY)
dec=sl.shapes.add_shape(MSO_SHAPE.RECTANGLE,0,Inches(3.8),prs.slide_width,Inches(0.1))
dec.fill.solid();dec.fill.fore_color.rgb=C_TEAL;dec.line.fill.background();dec.shadow.inherit=False
dec2=sl.shapes.add_shape(MSO_SHAPE.RECTANGLE,0,Inches(3.9),prs.slide_width,Inches(0.04))
dec2.fill.solid();dec2.fill.fore_color.rgb=C_GOLD;dec2.line.fill.background();dec2.shadow.inherit=False
tb(sl,"GENETICS CBD",1,1.2,11,0.7,size=22,color=C_GOLD,align=PP_ALIGN.CENTER)
tb(sl,"CHROMOSOMAL ANOMALIES",0.5,2.0,12.3,1.1,size=46,bold=True,color=C_WHITE,align=PP_ALIGN.CENTER)
tb(sl,"Definition  |  Down Syndrome  |  Jacob's Syndrome  |  Y-Linked Diseases  |  X-Linked Diseases",
   1,3.22,11.3,0.6,size=15,color=C_GOLD,align=PP_ALIGN.CENTER)
tb(sl,"Sources: Robbins & Kumar Basic Pathology | Thompson & Thompson Genetics 9th ed. | Emery's Elements of Medical Genetics",
   1,6.8,11.3,0.5,size=10,italic=True,color=RGBColor(0xAA,0xBB,0xCC),align=PP_ALIGN.CENTER)

# ── SLIDE 16 – DEFINITION ───────────────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"16. Chromosomal Anomalies: Definition","Abnormalities of chromosome number, structure, or both",col=C_NAVY)

# Numerical anomalies
tb(sl,"A. Numerical Abnormalities (Aneuploidy)",0.3,1.35,6.2,0.38,size=14,bold=True,color=C_NAVY)
numerical=[("Monosomy (2n-1)","Loss of 1 chromosome","45,X — Turner syndrome",C_RED),
           ("Trisomy (2n+1)","Extra chromosome","47,+21 — Down syndrome",C_ORANGE),
           ("Tetrasomy","Two extra of same type","48,XXXX",C_PURPLE),
           ("Polyploidy","Complete extra set (lethal)","Triploidy (69,XXX)",RGBColor(0x5D,0x6D,0x7E))]
for i,(name,def_,ex,col) in enumerate(numerical):
    yp=1.82+i*0.68
    cbox(sl,name,0.3,yp,2.2,0.55,col,size=11,bold=True)
    tb(sl,def_,2.6,yp+0.06,2.0,0.45,size=11,color=C_DARK)
    tb(sl,ex,4.65,yp+0.06,1.65,0.45,size=10,color=col,bold=True)

# Structural anomalies
tb(sl,"B. Structural Abnormalities",0.3,4.65,6.2,0.38,size=14,bold=True,color=C_TEAL)
structural=[("Deletion","Loss of segment","5p- (Cri-du-chat)",C_RED),
            ("Duplication","Extra copy","Dup 17p11.2 (CMT1A)",C_ORANGE),
            ("Translocation (Rob.)","Fusion of 2 acrocentrics","rob(14;21) in Down syndrome",C_TEAL),
            ("Translocation (Recip.)","Exchange between non-homologs","t(9;22) — Philadelphia chr",C_NAVY),
            ("Inversion","Reversed segment","inv(9)",C_PURPLE)]
for i,(name,def_,ex,col) in enumerate(structural):
    yp=5.1+i*0.38
    cbox(sl,name,0.3,yp,2.2,0.32,col,size=10,bold=True)
    tb(sl,def_,2.6,yp+0.02,2.0,0.32,size=10,color=C_DARK)
    tb(sl,ex,4.65,yp+0.02,1.65,0.32,size=9,color=col)

# Right panel – causes and frequency
tb(sl,"C. Special Categories",6.8,1.35,6.2,0.38,size=14,bold=True,color=C_NAVY)
special=[("Uniparental Disomy (UPD)","Both homologs from one parent","PWS/Angelman",C_ORANGE),
         ("Mosaicism","Two+ different cell lines","Mosaic Down",C_TEAL),
         ("Genomic imprinting","Epigenetic regulation disruption","PWS/AS",C_PURPLE)]
for i,(name,mech,ex,col) in enumerate(special):
    yp=1.82+i*0.78
    cbox(sl,name,6.8,yp,2.2,0.62,col,size=11,bold=True)
    tb(sl,mech,9.1,yp+0.06,2.5,0.55,size=11,color=C_DARK)
    tb(sl,ex,11.65,yp+0.06,1.5,0.55,size=10,color=col,bold=True)

# Causes
tb(sl,"Causes",6.8,4.22,6.2,0.38,size=14,bold=True,color=C_TEAL)
causes=["Nondisjunction (most common): failure of chromosomes to separate during meiosis I or II",
        "Advanced maternal age: strongly associated with most trisomies",
        "Chromosome breakage: radiation, chemical mutagens, errors in repair",
        "Unequal recombination at segmental duplications (e.g., 15q11-q13)"]
for i,c in enumerate(causes):
    tb(sl,f"• {c}",6.8,4.65+i*0.45,6.2,0.42,size=11,color=C_DARK)

freq=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(6.8),Inches(6.55),Inches(6.2),Inches(0.62))
freq.fill.solid();freq.fill.fore_color.rgb=C_NAVY;freq.line.fill.background();freq.shadow.inherit=False
tb(sl,"Frequency: ~1 in 160 live births have a chromosomal abnormality | ~50% of spontaneous abortions are chromosomally abnormal",
   6.9,6.6,6.0,0.52,size=11,color=C_WHITE)

foot(sl,"Thompson & Thompson Genetics 9th ed. | Emery's Elements of Medical Genetics | Robbins & Kumar Pathologic Basis of Disease")

# ── SLIDE 17 – DOWN SYNDROME ────────────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"17. Down Syndrome (Trisomy 21 / Mongolism)","Most common chromosomal disorder | 1 in 700 live births",col=C_TEAL)

# Karyotype types
tb(sl,"Karyotype Types",0.3,1.35,5.5,0.38,size=14,bold=True,color=C_NAVY)
kary=[("47,XX or XY,+21\n(Free trisomy)","~95%","Meiotic nondisjunction\n95% maternal origin",C_RED),
      ("46 with Robertsonian translocation","~4%","rob(14;21) — familial in some\nMaternal carrier 45,XX,rob(14;21)",C_ORANGE),
      ("Mosaic (46/47)","~1%","Mitotic nondisjunction in early embryo\nMilder phenotype possible",C_TEAL)]
for i,(ktype,pct,mech,col) in enumerate(kary):
    yp=1.82+i*1.0
    cbox(sl,ktype,0.3,yp,2.5,0.72,col,size=11,bold=True)
    cbox(sl,pct,2.88,yp+0.1,0.7,0.52,col,size=14,bold=True)
    tb(sl,mech,3.65,yp+0.1,2.0,0.52,size=10,color=C_DARK)

# Maternal age risk
tb(sl,"Maternal Age Risk",0.3,4.95,5.5,0.38,size=13,bold=True,color=C_TEAL)
age_risks=[("<20 yrs","1:1,550",C_LIME if False else C_GREEN),
           ("30 yrs","1:900",C_ORANGE),("35 yrs","1:385",C_ORANGE),
           ("40 yrs","1:100",C_RED),("≥45 yrs","1:25",C_RED)]
for i,(age,risk,col) in enumerate(age_risks):
    cbox(sl,age,0.3+i*1.08,5.38,0.9,0.45,C_NAVY,size=10,bold=True)
    cbox(sl,risk,0.3+i*1.08,5.88,0.9,0.45,col,size=10,bold=True)

# Clinical features
tb(sl,"Clinical Features",5.9,1.35,7.1,0.38,size=14,bold=True,color=C_NAVY)
cf_down=[
    ("FACIAL","Flat face, epicanthal folds, upslanting palpebral fissures\nBrushfield spots, macroglossia, small ears",C_TEAL),
    ("CNS","Moderate-mild intellectual disability (IQ 40–70)\nHypotonia (universal at birth)",C_NAVY),
    ("CARDIAC\n(40% affected)","AVSD 43% | VSD 32% | ASD 19% | ToF 6%\nLeading cause of death in infancy",C_RED),
    ("GI","Duodenal atresia ('double bubble') | Hirschsprung disease",C_ORANGE),
    ("HAEMATOLOGY","20× ALL risk | 500× AML risk | Transient myeloproliferative disorder",C_PURPLE),
    ("NEURODEGENERATION","Alzheimer disease in virtually ALL patients >40 yrs\n(APP gene × 3 → excess amyloid-β)",RGBColor(0x5D,0x6D,0x7E)),
    ("IMMUNOLOGY","Defective T-cell function → infections | Thyroid autoimmunity 15–20%",RGBColor(0x2E,0x86,0xAB)),
    ("LIFE EXPECTANCY","Median 47 years (was 25 yrs in 1983)\nImproved with cardiac surgery",C_GREEN),
]
for i,(sys,desc,col) in enumerate(cf_down):
    col_i=i%2; row_i=i//2
    xp=5.9+col_i*3.55; yp=1.82+row_i*1.18
    cbox(sl,sys,xp,yp,1.8,0.58,col,size=10,bold=True)
    tb(sl,desc,xp+1.85,yp+0.05,1.6,0.55,size=9,color=C_DARK)

# Prenatal screening
ps=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(0.3),Inches(6.48),Inches(5.5),Inches(0.7))
ps.fill.solid();ps.fill.fore_color.rgb=C_NAVY;ps.line.fill.background();ps.shadow.inherit=False
tb(sl,"Prenatal Screening:",0.4,6.53,2.0,0.3,size=12,bold=True,color=C_GOLD)
tb(sl,"cfDNA/NIPT (>99% sensitivity) | 1st trimester: NT + PAPP-A + β-hCG | 2nd trimester: Quad screen | Confirm: amniocentesis/CVS + karyotype",
   0.4,6.82,5.3,0.32,size=10,color=C_WHITE)

foot(sl,"Robbins & Kumar Pathologic Basis of Disease, p.163-165 | Thompson & Thompson Genetics 9th ed. | Emery's Elements of Medical Genetics")

# ── SLIDE 18 – JACOB'S SYNDROME ────────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"18. Jacob's Syndrome (47,XYY)","Sex chromosome aneuploidy | Extra Y chromosome | 1 in 1000 male births",col=C_ORANGE)

# Core facts
cbox(sl,"Karyotype: 47,XYY\nIncidence: 1 in 1,000 males\nCause: Nondisjunction in PATERNAL meiosis II\n(100% paternal origin — Y chromatids fail to separate)",
     0.3,1.35,4.5,1.35,C_NAVY,size=12,bold=True)

# Mosaicism note
ms=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(0.3),Inches(2.78),Inches(4.5),Inches(0.5))
ms.fill.solid();ms.fill.fore_color.rgb=RGBColor(0xFE,0xF9,0xE7);ms.line.color.rgb=C_ORANGE;ms.line.width=Pt(1.5);ms.shadow.inherit=False
tb(sl,"Mosaicism (46,XY/47,XYY): post-zygotic mitotic error — ~10% of cases; milder phenotype",
   0.4,2.83,4.3,0.4,size=11,color=C_DARK)

# Clinical features – 4 domains
tb(sl,"Clinical Features",0.3,3.38,4.5,0.38,size=14,bold=True,color=C_NAVY)
domains=[
    ("Physical",C_TEAL,["Tall stature (>1.88m at final height)",
                        "Macrocephaly | Hypertelorism","Clinodactyly (5th finger)",
                        "Macroorchidism | Macrodontia","Flat feet (pes planus) | Scoliosis"]),
    ("Neurodevelopment",C_ORANGE,["Normal IQ (slightly ↓ vs siblings)",
                                   "Language/reading delays (dyslexia)","Delayed motor milestones",
                                   "ADHD | Anxiety | Depression","Autism spectrum disorder risk"]),
    ("Medical",C_RED,["Asthma (increased incidence)","Seizures / tremors",
                       "Genitourinary anomalies (some)",
                       "Infertility: oligospermia (some)","Most reproduce with normal offspring karyotype"]),
    ("Behavioral",C_PURPLE,["Impulse control difficulties","Emotional dysregulation",
                              "Early studies: antisocial link (now questioned)",
                              "NOT necessarily violent/criminal","Many individuals fully normal"]),
]
for i,(dom,col,items) in enumerate(domains):
    col_i=i%2; row_i=i//2
    xp=0.3+col_i*2.25; yp=3.82+row_i*1.6
    cbox(sl,dom,xp,yp,2.0,0.45,col,size=11,bold=True)
    for j,item in enumerate(items):
        tb(sl,f"• {item}",xp,yp+0.5+j*0.28,2.1,0.26,size=9,color=C_DARK)

# Diagnosis & management
tb(sl,"Diagnosis & Management",5.0,1.35,8.0,0.38,size=14,bold=True,color=C_NAVY)
dm=[("Prenatal","NIPT, amniocentesis, CVS — karyotype 47,XYY confirmed"),
    ("Postnatal","Karyotype from blood lymphocytes | Median Dx age: ~17 yrs (infertility concern)"),
    ("Speech therapy","Early language/speech intervention for language delays"),
    ("Educational","Individualized educational support for learning difficulties"),
    ("Behavioral","CBT, behavioral therapy for impulse control"),
    ("Occupational","Therapy for motor delays"),
    ("Monitoring","Annual check for scoliosis | Endocrine evaluation if growth concerns"),
    ("Genetic counseling","Most offspring have normal karyotype; ART if infertile")]
for i,(cat,desc) in enumerate(dm):
    cbox(sl,cat,5.0,1.82+i*0.62,1.8,0.48,C_TEAL,size=10,bold=True)
    tb(sl,desc,6.9,1.86+i*0.62,6.2,0.46,size=10,color=C_DARK)

foot(sl,"NCBI Bookshelf NBK557699 | Cleveland Clinic | MedlinePlus Genetics | Emery's Elements of Medical Genetics")

# ── SLIDE 19 – Y-LINKED DISEASES ───────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"19. Y-Linked (Holandric) Diseases","Genes on the Y chromosome — father to ALL sons | NO daughters affected",col=C_GREEN)

# Definition box
cbox(sl,"Y-Linked Inheritance Rules:\n• Transmitted exclusively father → son (holandric)\n• ALL sons of affected father are affected\n• NO daughters affected (ever)\n• No female carriers",
     0.3,1.35,5.5,1.1,C_NAVY,size=12,bold=True)

# Y chromosome structure
tb(sl,"Y Chromosome Structure",0.3,2.55,5.5,0.38,size=13,bold=True,color=C_TEAL)
cbox(sl,"PAR1\n(Pseudoautosomal\nRegion 1)",0.3,2.98,1.8,0.85,C_TEAL,size=10,bold=True)
cbox(sl,"MSY\nMale-Specific\nY Region\n(Non-recombining)",2.2,2.98,1.8,0.85,C_NAVY,size=10,bold=True)
cbox(sl,"PAR2\n(Pseudoautosomal\nRegion 2)",4.1,2.98,1.5,0.85,C_TEAL,size=10,bold=True)
tb(sl,"PAR1/2: pair with X during meiosis — NOT truly Y-specific",0.3,3.9,5.5,0.35,size=10,italic=True,color=C_DARK)

# Key Y-linked genes
tb(sl,"Key Y-Linked Genes & Diseases",0.3,4.32,5.5,0.38,size=13,bold=True,color=C_NAVY)
y_genes=[("SRY","Yp11.3","Sex determination\n→ initiates male sex development","SRY mutations → 46,XY sex reversal (female phenotype)",C_RED),
         ("AZFa/b/c\n(Azoospermia\nFactor loci)","Yq11.2","Spermatogenesis — RNA binding\n(DAZ, RBMY, USP9Y)","Microdeletions → azoospermia/oligospermia → male infertility",C_ORANGE),
         ("Hypertrichosis\npinnae","Y (debated)","Hairy ear pinna — classical holandric teaching example","Father-to-all-sons transmission (now debated vs autosomal)",C_TEAL)]
for i,(gene,loc,func,dis,col) in enumerate(y_genes):
    cbox(sl,gene,0.3,4.78+i*0.62,1.1,0.52,col,size=10,bold=True)
    tb(sl,f"Loc: {loc}",1.48,4.8+i*0.62,0.9,0.25,size=9,color=C_DARK)
    tb(sl,func,1.48,5.0+i*0.62,2.2,0.35,size=9,color=C_DARK)
    tb(sl,dis,3.75,4.82+i*0.62,1.95,0.5,size=9,color=col,bold=True)

# Right panel – AZF deletions + Klinefelter
tb(sl,"Y Chromosome Microdeletions (Infertility)",5.9,1.35,7.1,0.38,size=14,bold=True,color=C_NAVY)
azf=[("AZFa deletion","Sertoli-cell-only syndrome — NO germ cells\nTESE: sperm retrieval UNLIKELY",C_RED),
     ("AZFb deletion","Spermatogenic arrest\nTESE: sperm retrieval UNLIKELY",C_ORANGE),
     ("AZFc deletion","Most common (50–60% of AZF dels)\nVariable severity — TESE often SUCCESSFUL",C_TEAL)]
for i,(del_,desc,col) in enumerate(azf):
    yp=1.82+i*1.0
    cbox(sl,del_,5.9,yp,2.3,0.55,col,size=11,bold=True)
    tb(sl,desc,8.3,yp+0.05,4.6,0.52,size=11,color=C_DARK)

# Prevalence
prev=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(5.9),Inches(4.95),Inches(7.1),Inches(0.5))
prev.fill.solid();prev.fill.fore_color.rgb=RGBColor(0xD5,0xF5,0xE3);prev.line.color.rgb=C_GREEN;prev.line.width=Pt(1.5);prev.shadow.inherit=False
tb(sl,"AZF deletion prevalence: ~7–10% of azoospermic men | ~5% of severely oligospermic men",
   6.0,5.0,6.9,0.4,size=11,bold=True,color=C_DARK)

# Klinefelter
tb(sl,"Klinefelter Syndrome (47,XXY) — for comparison",5.9,5.55,7.1,0.38,size=13,bold=True,color=C_NAVY)
kf=["Karyotype: 47,XXY (most common); XXYY, XXXY, XXXXY (increasingly severe)",
    "Incidence: 1 in 500–1,000 male births",
    "Features: tall stature | small testes | azoospermia | gynecomastia | ↓ testosterone | learning difficulties",
    "NOT Y-linked inheritance — involves extra sex chromosome; often de novo nondisjunction"]
for i,k in enumerate(kf):
    tb(sl,f"• {k}",5.9,5.98+i*0.3,7.1,0.28,size=10,color=C_DARK)

foot(sl,"Emery's Elements of Medical Genetics | Thompson & Thompson Genetics 9th ed. | NCBI/GeneReviews")

# ── SLIDE 20 – X-LINKED DISEASES ────────────────────────────────────────────
sl=prs.slides.add_slide(BLANK);bg(sl)
hdr(sl,"20. X-Linked Diseases","Genes on the X chromosome — hemizygous expression in males",col=C_RED)

# Lyon hypothesis box
lh=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(0.3),Inches(1.35),Inches(12.7),Inches(0.52))
lh.fill.solid();lh.fill.fore_color.rgb=RGBColor(0xFD,0xED,0xEC);lh.line.color.rgb=C_RED;lh.line.width=Pt(2);lh.shadow.inherit=False
tb(sl,"Lyon Hypothesis (X-Inactivation): In females, one X is randomly inactivated per somatic cell at ~16 days post-fertilization → Barr body. Skewed X-inactivation (>90:10) can cause manifesting carriers.",
   0.4,1.4,12.4,0.42,size=11,color=C_DARK)

# XLR rules
tb(sl,"X-Linked RECESSIVE (XLR) Key Rules",0.3,1.97,5.5,0.38,size=13,bold=True,color=C_NAVY)
xlr_rules=["Predominantly affects MALES (hemizygous)",
           "Females usually asymptomatic CARRIERS (heterozygous)",
           "Carrier mother: 50% sons affected | 50% daughters carriers",
           "Affected father: ALL daughters carriers | NO sons affected",
           "NO male-to-male transmission (KEY feature)",
           "Rare affected females: Turner syndrome, homozygous XLR, skewed X-inactivation"]
for i,r in enumerate(xlr_rules):
    cbox(sl,str(i+1),0.3,2.42+i*0.44,0.4,0.37,C_RED,size=12,bold=True)
    tb(sl,r,0.82,2.44+i*0.44,4.8,0.36,size=10,color=C_DARK)

# XLD box
xld=sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,Inches(0.3),Inches(5.12),Inches(5.5),Inches(1.6))
xld.fill.solid();xld.fill.fore_color.rgb=RGBColor(0xD5,0xF5,0xE3);xld.line.color.rgb=C_GREEN;xld.line.width=Pt(1.5);xld.shadow.inherit=False
tb(sl,"X-Linked DOMINANT (XLD):",0.4,5.17,3.0,0.35,size=12,bold=True,color=C_GREEN)
xld_ex=[("Rett Syndrome","MECP2 — progressive neurological disorder; almost exclusively females (males lethal)"),
         ("Incontinentia Pigmenti","IKBKG — skin/dental/CNS/eye; males die in utero"),
         ("Hypophosphatemic Rickets","PHEX — phosphate-wasting; affects both sexes")]
for i,(name,desc) in enumerate(xld_ex):
    tb(sl,f"• {name}:",0.4,5.56+i*0.36,2.1,0.33,size=10,bold=True,color=C_GREEN)
    tb(sl,desc,2.5,5.56+i*0.36,3.2,0.33,size=10,color=C_DARK)

# Right panel – major XLR diseases table
tb(sl,"Major X-Linked Recessive Diseases",5.9,1.97,7.1,0.38,size=13,bold=True,color=C_NAVY)
xlr_diseases=[
    ("Duchenne MD","DMD (dystrophin) Xp21.2","Progressive muscle wasting; Gowers' sign; wheelchair teens; dilated CM",C_RED),
    ("Haemophilia A","F8 (Factor VIII) Xq28","Severe bleeding; haemarthroses; ↓/absent FVIII",C_RED),
    ("Haemophilia B","F9 (Factor IX) Xq27.1","Christmas disease; similar to Hemo A",C_ORANGE),
    ("Fragile X Syndrome","FMR1 (CGG repeat exp.) Xq27.3","Most common inherited ID; macroorchidism; autism; large ears",C_PURPLE),
    ("Colour blindness","OPN1LW/MW Xq28","Most common XL; ~8% males; red-green deficiency",C_TEAL),
    ("G6PD Deficiency","G6PD Xq28","Haemolytic anaemia: drugs/infections/fava beans",C_ORANGE),
    ("Fabry Disease","GLA (α-galactosidase A) Xq22","Lysosomal storage; angiokeratomas; renal failure; cardiac",C_NAVY),
    ("Lesch-Nyhan","HPRT1 Xq26","Gout + ID + self-mutilation; HGPRT deficiency",C_RED),
    ("X-linked Agammaglob.","BTK (Bruton's TK) Xq21.33","Absent B cells; recurrent bacterial infections",C_GREEN),
    ("Wiskott-Aldrich","WAS Xp11.23","Triad: eczema + thrombocytopenia + immunodeficiency",C_PURPLE),
]
for i,(disease,gene,features,col) in enumerate(xlr_diseases):
    col_i=i%2; row_i=i//2
    xp=5.9+col_i*3.55; yp=2.42+row_i*0.92
    cbox(sl,disease,xp,yp,2.0,0.5,col,size=10,bold=True)
    tb(sl,gene,xp+2.05,yp+0.01,1.3,0.28,size=8,color=col,bold=True)
    tb(sl,features,xp+2.05,yp+0.26,1.45,0.32,size=8,color=C_DARK)

foot(sl,"Emery's Elements of Medical Genetics | Thompson & Thompson Genetics 9th ed. | Robbins & Kumar Pathologic Basis of Disease")

# REFERENCES
sl=prs.slides.add_slide(BLANK);bg(sl,C_NAVY)
hdr(sl,"References","Chromosomal Anomalies",col=C_TEAL)
refs3=["1. Robbins R, Kumar V. Robbins & Kumar Basic Pathology. 11th ed. Elsevier; 2023. p.163-165.",
       "2. Thompson MW et al. Thompson & Thompson Genetics and Genomics in Medicine. 9th ed. Elsevier; 2023.",
       "3. Turnpenny P, Ellard S. Emery's Elements of Medical Genetics and Genomics. 16th ed. Elsevier; 2022.",
       "4. Bull MJ. Down syndrome. N Engl J Med. 2020;382:2344-2352.",
       "5. Tartaglia NR et al. 47,XYY syndrome. StatPearls/NCBI Bookshelf NBK557699. 2023.",
       "6. Cleveland Clinic. 47,XYY Syndrome (Jacobs Syndrome). my.clevelandclinic.org. 2024.",
       "7. GeneReviews: 47,XYY Syndrome. MedlinePlus Genetics. NIH.",
       "8. Vogt PH et al. Human Y chromosome azoospermia factors (AZF). Hum Reprod. 1996;11:1459-1466."]
for i,r in enumerate(refs3):
    tb(sl,r,0.5,1.4+i*0.65,12.3,0.58,size=12,color=C_WHITE)

buf=BytesIO();prs.save(buf)
with open("/tmp/workspace/genetics-cbd/PPT4_Chromosomal_Anomalies.pptx","wb") as f:
    f.write(buf.getvalue())
print("PPT4 saved")

Running Command

cd /tmp/workspace/genetics-cbd && python make_ppt1.py && python make_ppt2.py && python make_ppt3.py && python make_ppt4.py

Editing File

~/genetics-cbd/make_ppt2.py

Successfully replaced 1 instance(s) of the string in '/tmp/workspace/genetics-cbd/make_ppt2.py'

Running Command

cd /tmp/workspace/genetics-cbd && python make_ppt2.py && python make_ppt3.py && python make_ppt4.py

Editing File

~/genetics-cbd/make_ppt2.py

Successfully replaced 1 instance(s) of the string in '/tmp/workspace/genetics-cbd/make_ppt2.py'

Running Command

cd /tmp/workspace/genetics-cbd && python make_ppt2.py && python make_ppt3.py && python make_ppt4.py && echo "ALL DONE" && ls -lh *.pptx

Running Command

grep -n '"[0-9]' /tmp/workspace/genetics-cbd/make_ppt2.py | head -30

Again

Running Command

ls /tmp/workspace/genetics-cbd/

Writing File

~/genetics-cbd/make_ppt2.py

"""PPT 2: Multifactorial Congenital Malformations - clean version"""
from pptx import Presentation
from pptx.util import Inches, Pt
from pptx.dml.color import RGBColor
from pptx.enum.text import PP_ALIGN, MSO_ANCHOR
from pptx.enum.shapes import MSO_SHAPE, MSO_CONNECTOR
from io import BytesIO

C_NAVY   = RGBColor(0x0D,0x2B,0x6E)
C_TEAL   = RGBColor(0x00,0x7B,0x8A)
C_LIME   = RGBColor(0x6A,0xB1,0x87)
C_ORANGE = RGBColor(0xE8,0x8B,0x2E)
C_WHITE  = RGBColor(0xFF,0xFF,0xFF)
C_LIGHT  = RGBColor(0xF0,0xF6,0xFB)
C_DARK   = RGBColor(0x1A,0x1A,0x2E)
C_RED    = RGBColor(0xC0,0x39,0x2B)
C_GOLD   = RGBColor(0xF5,0xCB,0x5C)
C_PURPLE = RGBColor(0x7B,0x35,0x7B)
C_GREEN  = RGBColor(0x1A,0x7A,0x4A)

prs = Presentation()
prs.slide_width  = Inches(13.333)
prs.slide_height = Inches(7.5)
BLANK = prs.slide_layouts[6]

def bg(slide, color=C_LIGHT):
    s = slide.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, 0, prs.slide_width, prs.slide_height)
    s.fill.solid(); s.fill.fore_color.rgb = color
    s.line.fill.background(); s.shadow.inherit = False

def hdr(slide, title, subtitle="", col=C_NAVY):
    b = slide.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, 0, prs.slide_width, Inches(1.25))
    b.fill.solid(); b.fill.fore_color.rgb = col
    b.line.fill.background(); b.shadow.inherit = False
    t = slide.shapes.add_textbox(Inches(0.3), Inches(0.05), Inches(12), Inches(0.7))
    p = t.text_frame.paragraphs[0]; p.text = title
    r = p.runs[0]; r.font.size = Pt(28); r.font.bold = True
    r.font.color.rgb = C_WHITE; r.font.name = "Calibri"
    if subtitle:
        t2 = slide.shapes.add_textbox(Inches(0.35), Inches(0.78), Inches(12), Inches(0.45))
        p2 = t2.text_frame.paragraphs[0]; p2.text = subtitle
        r2 = p2.runs[0]; r2.font.size = Pt(15); r2.font.color.rgb = C_GOLD; r2.font.name = "Calibri"

def add_text(slide, text, x, y, w, h, size=13, bold=False, color=C_DARK,
             align=PP_ALIGN.LEFT, italic=False, wrap=True):
    box = slide.shapes.add_textbox(Inches(x), Inches(y), Inches(w), Inches(h))
    tf = box.text_frame; tf.word_wrap = wrap
    p = tf.paragraphs[0]; p.text = text; p.alignment = align
    r = p.runs[0]; r.font.size = Pt(size); r.font.bold = bold
    r.font.color.rgb = color; r.font.name = "Calibri"; r.font.italic = italic

def cbox(slide, text, x, y, w, h, bg_c, tc=C_WHITE, size=12, bold=False):
    s = slide.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                               Inches(x), Inches(y), Inches(w), Inches(h))
    s.fill.solid(); s.fill.fore_color.rgb = bg_c
    s.line.fill.background(); s.shadow.inherit = False
    tf = s.text_frame; tf.word_wrap = True; tf.vertical_anchor = MSO_ANCHOR.MIDDLE
    p = tf.paragraphs[0]; p.text = text; p.alignment = PP_ALIGN.CENTER
    r = p.runs[0]; r.font.size = Pt(size); r.font.color.rgb = tc
    r.font.bold = bold; r.font.name = "Calibri"

def foot(slide, ref):
    ln = slide.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,
                                    Inches(0.3), Inches(7.15), Inches(13), Inches(7.15))
    ln.line.color.rgb = C_TEAL; ln.line.width = Pt(1)
    add_text(slide, ref, 0.3, 7.18, 12.7, 0.3, size=9, italic=True,
             color=RGBColor(0x55, 0x55, 0x55))

# ── TITLE ────────────────────────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl, C_NAVY)
dec = sl.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, Inches(3.8), prs.slide_width, Inches(0.1))
dec.fill.solid(); dec.fill.fore_color.rgb = C_TEAL
dec.line.fill.background(); dec.shadow.inherit = False
dec2 = sl.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, Inches(3.9), prs.slide_width, Inches(0.04))
dec2.fill.solid(); dec2.fill.fore_color.rgb = C_GOLD
dec2.line.fill.background(); dec2.shadow.inherit = False
add_text(sl, "GENETICS CBD", 1, 1.2, 11, 0.6, size=22, color=C_GOLD, align=PP_ALIGN.CENTER)
add_text(sl, "MULTIFACTORIAL CONGENITAL\nMALFORMATIONS",
         0.5, 1.85, 12.3, 1.5, size=40, bold=True, color=C_WHITE, align=PP_ALIGN.CENTER)
add_text(sl, "Definition  |  Neuropsychiatric & Bipolar Disease  |  Coronary Artery Disease  |  Modifier Genes  |  Digenic Inheritance",
         1, 3.6, 11.3, 0.6, size=15, color=C_GOLD, align=PP_ALIGN.CENTER)
add_text(sl, "Sources: Thompson & Thompson Genetics 9th ed. | Emery's Elements of Medical Genetics | Goldman-Cecil Medicine",
         1, 6.8, 11.3, 0.5, size=10, italic=True,
         color=RGBColor(0xAA, 0xBB, 0xCC), align=PP_ALIGN.CENTER)

# ── SLIDE 6: DEFINITION ──────────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "6. Multifactorial Congenital Malformations",
    "Polygenic + environmental threshold model", col=C_TEAL)

add_text(sl,
    "Definition: Conditions caused by interaction of MULTIPLE GENES (polygenic) with ENVIRONMENTAL FACTORS. "
    "No single gene or environmental exposure alone is sufficient — disease appears only when combined liability exceeds a THRESHOLD.",
    0.3, 1.35, 12.7, 0.65, size=13, color=C_DARK)

# Threshold model diagram (abstract bell shape with colour blocks)
add_text(sl, "Threshold Model of Liability", 0.3, 2.1, 5.5, 0.38, size=14, bold=True, color=C_NAVY)
# simulate a bell-curve with stacked ovals
for i, (yw, xo, col) in enumerate([
    (0.22, 1.3, RGBColor(0xD6,0xEA,0xF8)),
    (0.30, 1.0, RGBColor(0xA9,0xCC,0xE3)),
    (0.36, 0.7, RGBColor(0x5D,0xAD,0xE8)),
    (0.30, 1.0, RGBColor(0xA9,0xCC,0xE3)),
    (0.22, 1.3, RGBColor(0xD6,0xEA,0xF8)),
]):
    s = sl.shapes.add_shape(MSO_SHAPE.OVAL, Inches(0.4 + xo), Inches(2.55 + i*0.28),
                            Inches(3.8 - xo*0.5), Inches(yw))
    s.fill.solid(); s.fill.fore_color.rgb = col
    s.line.fill.background(); s.shadow.inherit = False
# threshold line
ln = sl.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,
                              Inches(3.4), Inches(2.5), Inches(3.4), Inches(4.05))
ln.line.color.rgb = C_RED; ln.line.width = Pt(3)
add_text(sl, "THRESHOLD", 3.45, 2.52, 1.8, 0.35, size=11, bold=True, color=C_RED)
add_text(sl, "Normal population",  0.4, 4.1, 2.2, 0.35, size=11, italic=True, color=C_TEAL)
add_text(sl, "Affected", 3.5, 4.1, 1.5, 0.35, size=11, italic=True, color=C_RED)
add_text(sl, "Liability (genes + environment) →", 0.4, 4.5, 5.0, 0.35, size=11, color=C_DARK)

# Characteristics
add_text(sl, "Key Characteristics", 6.1, 1.35, 6.9, 0.38, size=14, bold=True, color=C_NAVY)
chars = [
    "Risk is HIGHER in 1st-degree relatives than the general population",
    "Risk DROPS RAPIDLY with decreasing degree of relationship",
    "Risk INCREASES if multiple family members are affected",
    "Carter Effect: higher risk if proband is the less-commonly affected sex",
    "More severe the malformation → higher recurrence risk",
    "No single Mendelian pattern — polygenic + multifactorial",
]
for i, c in enumerate(chars):
    cbox(sl, str(i+1), 6.1, 1.82 + i*0.72, 0.45, 0.55, C_TEAL, size=13, bold=True)
    add_text(sl, c, 6.65, 1.86 + i*0.72, 6.4, 0.52, size=12, color=C_DARK)

# Table of malformations
add_text(sl, "Common Malformations with Multifactorial Inheritance",
         0.3, 5.02, 5.5, 0.38, size=13, bold=True, color=C_TEAL)
items = [
    ("Congenital heart defects (all)", "4–8 per 1000"),
    ("Neural tube defects", "2–10 per 1000"),
    ("Cleft lip ± palate", "0.4–1.7 per 1000"),
    ("Pyloric stenosis (males)", "5 per 1000"),
    ("Hip dislocation (females)", "2 per 1000"),
    ("Ventricular septal defect", "1.7 per 1000"),
]
for i, (name, inc) in enumerate(items):
    ci = i % 3; ri = i // 2
    xp = 0.3 + ci * 1.75; yp = 5.48 + ri * 0.55
    cbox(sl, name, xp, yp, 1.6, 0.45, C_NAVY, size=9, bold=True)
    add_text(sl, inc, xp, yp + 0.47, 1.6, 0.3, size=9, color=C_ORANGE, bold=True)

foot(sl, "Thompson & Thompson Genetics 9th ed., p.181-182 | Emery's Elements of Medical Genetics | Robbins & Kumar Basic Pathology")

# ── SLIDE 7: NEUROPSYCHIATRIC / BIPOLAR ──────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "7. Neuropsychiatric Disorders & Bipolar Disease",
    "Schizophrenia and Bipolar Disorder — complex multifactorial traits", col=C_PURPLE)

# Schizophrenia
cbox(sl, "SCHIZOPHRENIA", 0.3, 1.35, 6.0, 0.52, C_NAVY, size=16, bold=True)
add_text(sl, "Prevalence: 1% worldwide | Onset: late adolescence/young adulthood",
         0.3, 1.92, 6.0, 0.38, size=12, color=C_DARK)
add_text(sl, "Features: disordered thought, emotion, social relationships; delusions; hallucinations",
         0.3, 2.3, 6.0, 0.4, size=12, color=C_DARK)

add_text(sl, "Recurrence Risks in Schizophrenia", 0.3, 2.82, 6.0, 0.35, size=13, bold=True, color=C_TEAL)
risks = [
    ("Child of 2 affected parents", "46%", C_RED),
    ("Child of 1 affected parent",  "9–16%", C_ORANGE),
    ("Sibling",                     "8–14%", C_ORANGE),
    ("Nephew / niece",              "1–4%",  C_TEAL),
    ("First cousin",                "2–6%",  C_LIME),
]
for i, (rel, risk, col) in enumerate(risks):
    yp = 3.22 + i * 0.5
    cbox(sl, rel,  0.3, yp, 4.2, 0.42, C_LIGHT, tc=C_DARK, size=11)
    cbox(sl, risk, 4.6, yp, 1.6, 0.42, col,     size=13, bold=True)

# Twin concordance
cbox(sl, "MZ: 40–60%", 0.3, 5.75, 2.8, 0.48, C_TEAL, size=13, bold=True)
cbox(sl, "DZ: 10–16%", 3.2, 5.75, 2.8, 0.48, C_ORANGE, size=13, bold=True)
add_text(sl, "22q11 deletion: 25% lifetime risk of schizophrenia",
         0.3, 6.3, 6.0, 0.38, size=11, italic=True, color=C_DARK)

# Bipolar
cbox(sl, "BIPOLAR DISORDER (Manic-Depressive Illness)", 6.5, 1.35, 6.5, 0.52, C_ORANGE, size=14, bold=True, tc=C_DARK)
add_text(sl, "Prevalence: 1–2% worldwide | Heritability: ~70–80%\nCycles of mania and depression",
         6.5, 1.92, 6.5, 0.55, size=12, color=C_DARK)

add_text(sl, "Genetic Evidence", 6.5, 2.6, 6.5, 0.35, size=13, bold=True, color=C_NAVY)
bp = [
    ("MZ concordance",          "40–70%",            C_ORANGE),
    ("DZ concordance",          "15–25%",            C_LIME),
    ("1st-degree relative risk","~10× general pop",  C_RED),
    ("Heritability",            "~70–80%",           C_TEAL),
]
for i, (label, val, col) in enumerate(bp):
    xp = 6.5 + (i % 2) * 3.2; yp = 3.02 + (i // 2) * 0.72
    cbox(sl, label, xp, yp, 2.9, 0.45, col, size=11, bold=True)
    add_text(sl, val, xp + 0.1, yp + 0.48, 2.8, 0.3, size=12, bold=True, color=col)

add_text(sl, "GWAS Loci (Bipolar Disorder)", 6.5, 4.62, 6.5, 0.35, size=13, bold=True, color=C_NAVY)
loci = [
    "CACNA1C — voltage-gated calcium channel",
    "ANK3 — ankyrin G, axon initial segment",
    "NCAN — neurocan ECM glycoprotein",
    "TRANK1 | SYNE1 — risk loci",
    "Overlapping genetic architecture with schizophrenia (cross-disorder genetics)",
]
for i, l in enumerate(loci):
    add_text(sl, f"• {l}", 6.5, 5.02 + i * 0.38, 6.5, 0.36, size=11, color=C_DARK)

ge = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                         Inches(0.3), Inches(6.78), Inches(12.7), Inches(0.42))
ge.fill.solid(); ge.fill.fore_color.rgb = RGBColor(0xE8, 0xF4, 0xF8)
ge.line.color.rgb = C_TEAL; ge.line.width = Pt(1); ge.shadow.inherit = False
add_text(sl, "Gene × Environment Triggers: childhood trauma | sleep disruption | cannabis | obstetric complications | urban birth",
         0.4, 6.82, 12.4, 0.35, size=11, color=C_NAVY)

foot(sl, "Thompson & Thompson Genetics 9th ed., p.182-183 | Goldman-Cecil Medicine, International Edition")

# ── SLIDE 8: CORONARY ARTERY DISEASE ─────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "8. Coronary Artery Disease (CAD)",
    "Most common cause of death globally — complex multifactorial disease", col=C_RED)

add_text(sl, "Genetic Evidence from Twin Studies", 0.3, 1.35, 6.2, 0.38, size=14, bold=True, color=C_NAVY)
headers = ["Twin pair", "Concordance", "Relative risk vs. pop."]
for i, h in enumerate(headers):
    cbox(sl, h, 0.3 + i*2.0, 1.82, 1.85, 0.42, C_NAVY, size=11, bold=True)
twin_data = [
    ("Male MZ twins",   "39%", "6–8×"),
    ("Male DZ twins",   "26%", "3×"),
    ("Female MZ twins", "44%", "15×"),
    ("Female DZ twins", "14%", "2.6×"),
]
for i, (pair, conc, rr) in enumerate(twin_data):
    yp = 2.3 + i * 0.5
    bg_cols = [C_LIGHT, C_ORANGE, C_RED]
    for j, (val, bgc) in enumerate(zip([pair, conc, rr], bg_cols)):
        cbox(sl, val, 0.3 + j*2.0, yp, 1.85, 0.42, bgc,
             tc=C_DARK if bgc == C_LIGHT else C_WHITE, size=11, bold=(j > 0))

add_text(sl, "Stepwise Pathway — Genetic Factors", 0.3, 4.62, 6.2, 0.38, size=13, bold=True, color=C_TEAL)
stages = [
    ("Lipid metabolism",    "APOE, LDLR, APOC3, LPA (lipoprotein(a))",              C_TEAL),
    ("Vasoactivity",        "ACE (angiotensin-converting enzyme), AGTR1",            C_ORANGE),
    ("Coagulation",         "Factor V Leiden (R506Q), Prothrombin G20210A",          C_RED),
    ("Inflammation",        "IL-6, CRP, TNF-alpha loci",                             C_PURPLE),
    ("Endothelial function","NOS3 (endothelial nitric oxide synthase)",              C_GREEN),
]
for i, (stage, genes, col) in enumerate(stages):
    yp = 5.05 + i * 0.38
    cbox(sl, stage, 0.3, yp, 2.0, 0.32, col, size=10, bold=True)
    add_text(sl, genes, 2.4, yp + 0.02, 4.1, 0.3, size=10, color=C_DARK)

# Right panel
add_text(sl, "Environmental Risk Factors", 6.6, 1.35, 6.4, 0.38, size=14, bold=True, color=C_NAVY)
env = ["Diet: saturated fats, trans fats",
       "Physical inactivity",
       "Smoking",
       "Obesity & type 2 diabetes mellitus",
       "Systemic inflammation"]
for i, e in enumerate(env):
    cbox(sl, e, 6.6, 1.82 + i*0.55, 6.2, 0.45, C_LIGHT, tc=C_DARK, size=12)

add_text(sl, "Key GWAS Findings", 6.6, 4.65, 6.4, 0.38, size=14, bold=True, color=C_TEAL)
gwas = [
    "9p21.3 locus — strongest replicated CAD locus (CDKN2A/CDKN2B)",
    ">300 independent loci identified genome-wide",
    "Polygenic Risk Scores (PRS) show clinical utility",
    "Familial Hypercholesterolaemia: LDLR mutations (AD) → markedly elevated LDL",
    "Intermediate traits (HTN, DM, obesity) each have additional genetic architecture",
]
for i, g in enumerate(gwas):
    add_text(sl, f"• {g}", 6.6, 5.1 + i*0.42, 6.4, 0.4, size=11, color=C_DARK)

foot(sl, "Thompson & Thompson Genetics 9th ed., p.183-184 | Goldman-Cecil Medicine")

# ── SLIDE 9: MODIFIER GENES ──────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "9. Modifier Genes",
    "Secondary gene loci that modulate disease severity without causing the disease", col=C_TEAL)

add_text(sl,
    "Definition: Modifier genes are genes whose allelic variants affect the EXPRESSION, SEVERITY, or PHENOTYPE "
    "of a disease caused by mutations in a DIFFERENT primary gene. They do not cause the disease themselves.",
    0.3, 1.35, 12.7, 0.65, size=13, color=C_DARK)

cbox(sl, "CLASSIC EXAMPLE: CYSTIC FIBROSIS (CF)",
     0.3, 2.1, 12.7, 0.52, C_NAVY, size=15, bold=True)
add_text(sl, "Primary gene: CFTR  |  Variable phenotype NOT fully explained by CFTR genotype alone",
         0.3, 2.68, 12.7, 0.38, size=13, color=C_DARK)

for i, (name, desc, effect, col) in enumerate([
    ("MBL2\n(Mannose-Binding Lectin 2)",
     "Innate immunity plasma protein — binds pathogens, aids phagocytosis & complement activation\n"
     "Low MBL2 alleles → reduced innate immunity → worse Pseudomonas containment in CF airways",
     "Low MBL2 alleles → WORSE pulmonary outcome in CF", C_TEAL),
    ("TGFB1\n(Transforming Growth Factor-β)",
     "High TGFβ-producing alleles → increased lung fibrosis/scarring\n"
     "after chronic neutrophilic inflammation in CF airways",
     "High TGFB1 alleles → WORSE FEV1 decline in CF", C_ORANGE),
]):
    xp = 0.3 + i * 6.4
    cbox(sl, name, xp, 3.18, 2.3, 0.85, col, size=12, bold=True)
    add_text(sl, desc, xp + 2.4, 3.22, 3.8, 0.8, size=11, color=C_DARK)
    cbox(sl, effect, xp, 4.1, 6.2, 0.48, C_LIGHT, tc=col, size=11, bold=True)

note = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                           Inches(0.3), Inches(4.68), Inches(12.7), Inches(0.52))
note.fill.solid(); note.fill.fore_color.rgb = RGBColor(0xE8, 0xF4, 0xF8)
note.line.color.rgb = C_TEAL; note.line.width = Pt(1); note.shadow.inherit = False
add_text(sl,
    "CF Lung Disease Heritability: ~50% (MZ vs DZ twins in CF patients) — INDEPENDENT of CFTR allele; "
    "confirms ~50% of lung disease severity is due to genes OTHER than CFTR",
    0.4, 4.73, 12.4, 0.42, size=11, bold=True, color=C_NAVY)

add_text(sl, "Further Examples of Modifier Genes", 0.3, 5.32, 12.7, 0.38, size=14, bold=True, color=C_NAVY)
headers2 = ["Primary Disease", "Modifier Gene", "Effect on Phenotype"]
for i, h in enumerate(headers2):
    cbox(sl, h, 0.3 + i*4.2, 5.75, 4.0, 0.38, C_NAVY, size=11, bold=True)
rows = [
    ("Cystic fibrosis",                 "MBL2 / TGFB1",                 "Pulmonary disease severity"),
    ("Sickle cell disease",             "BCL11A, HBG (fetal Hb regulators)", "Severity of crises"),
    ("Familial hypercholesterolaemia",  "APOE genotype",                 "Cardiovascular severity"),
    ("Huntington disease",              "MSH3 (DNA mismatch repair)",    "Age of onset modulation"),
]
for i, (pd, mg, eff) in enumerate(rows):
    yp = 6.18 + i * 0.3
    for j, (val, bgc) in enumerate(zip([pd, mg, eff],
                                       [C_LIGHT, RGBColor(0xD6,0xEA,0xF8), RGBColor(0xD5,0xF5,0xE3)])):
        cbox(sl, val, 0.3 + j*4.2, yp, 4.0, 0.28, bgc, tc=C_DARK, size=10)

foot(sl, "Thompson & Thompson Genetics 9th ed., p.185 | Goldman-Cecil Medicine | Harrison's Principles 22E")

# ── SLIDE 10: DIGENIC INHERITANCE ────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "10. Digenic Inheritance",
    "Simplest multigenic inheritance — disease requires mutations at TWO different loci", col=C_NAVY)

add_text(sl,
    "Definition: Disease manifests ONLY when pathogenic variants at TWO DIFFERENT GENE LOCI are combined. "
    "Heterozygous variants at either locus alone are insufficient — only the co-occurrence of both causes the phenotype.",
    0.3, 1.35, 12.7, 0.65, size=13, color=C_DARK)

# Diagram
cbox(sl, "Gene A\n(Heterozygous)\nCarrier — unaffected",
     0.5, 2.15, 2.8, 1.05, C_TEAL, size=12, bold=True)
add_text(sl, "+", 3.4, 2.45, 0.5, 0.55, size=24, bold=True, color=C_DARK, align=PP_ALIGN.CENTER)
cbox(sl, "Gene B\n(Heterozygous)\nCarrier — unaffected",
     4.0, 2.15, 2.8, 1.05, C_ORANGE, size=12, bold=True)
add_text(sl, "=", 6.9, 2.45, 0.5, 0.55, size=24, bold=True, color=C_DARK, align=PP_ALIGN.CENTER)
cbox(sl, "DISEASE\n(Both mutations present together)",
     7.5, 2.15, 2.8, 1.05, C_RED, size=12, bold=True)
# neither alone
cbox(sl, "Gene A alone → NORMAL",  0.5,  3.35, 2.8, 0.38, C_LIGHT, tc=C_TEAL, size=11, bold=True)
cbox(sl, "Gene B alone → NORMAL",  4.0,  3.35, 2.8, 0.38, C_LIGHT, tc=C_ORANGE, size=11, bold=True)
cbox(sl, "Both together → DISEASE", 7.5, 3.35, 2.8, 0.38, C_RED, size=11, bold=True)

# Characteristics
add_text(sl, "Key Characteristics", 0.3, 3.95, 5.5, 0.38, size=14, bold=True, color=C_NAVY)
chars = [
    "Neither mutation alone causes disease",
    "Parents carrying one mutation each are UNAFFECTED",
    "Child inheriting BOTH mutations has 25% risk (if parents carry at different loci)",
    "Appears sporadic/recessive-like in pedigrees",
    "Key distinction: AR = 2 mutations SAME locus; Digenic = 1 mutation at EACH of 2 DIFFERENT loci",
]
for i, c in enumerate(chars):
    cbox(sl, str(i+1), 0.3, 4.38 + i*0.5, 0.42, 0.42, C_TEAL, size=13, bold=True)
    add_text(sl, c, 0.82, 4.4 + i*0.5, 5.0, 0.44, size=11, color=C_DARK)

# Examples
add_text(sl, "Clinical Examples", 6.4, 3.95, 6.6, 0.38, size=14, bold=True, color=C_NAVY)
examples = [
    ("Digenic Retinitis Pigmentosa", C_RED,
     "ROM1 + PRPH2 (peripherin)\nEither gene alone = normal vision; both together = RP"),
    ("Waardenburg Syndrome Type III", C_PURPLE,
     "PAX3 + MITF heterozygosity\nBoth required for the full phenotype"),
    ("Bardet-Biedl Syndrome", C_ORANGE,
     "Mutations at 2+ BBS loci (oligogenic/triallelic)\nIllustrates extension to oligogenic inheritance"),
    ("Hereditary Deafness (GJB2/GJB6)", C_TEAL,
     "Connexin 26 + Connexin 30\nDeletion of one + mutation in other → deafness"),
]
for i, (name, col, desc) in enumerate(examples):
    yp = 4.42 + i * 0.65
    cbox(sl, name, 6.4, yp, 6.4, 0.42, col, size=11, bold=True)
    add_text(sl, desc, 6.5, yp + 0.45, 6.2, 0.4, size=10, color=C_DARK)

cs = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                         Inches(0.3), Inches(6.82), Inches(12.7), Inches(0.42))
cs.fill.solid(); cs.fill.fore_color.rgb = C_NAVY
cs.line.fill.background(); cs.shadow.inherit = False
add_text(sl,
    "Clinical Significance: Explains sporadic cases in single-carrier families | "
    "Critical for genomic sequencing interpretation — VUS at two loci may act diigenically",
    0.4, 6.87, 12.4, 0.35, size=11, color=C_WHITE)

foot(sl, "Emery's Elements of Medical Genetics (citing Schäffer, J Med Genet 2013) | Thompson & Thompson Genetics 9th ed.")

# ── REFERENCES ───────────────────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl, C_NAVY)
hdr(sl, "References", "Multifactorial Congenital Malformations", col=C_TEAL)
refs = [
    "1. Thompson MW et al. Thompson & Thompson Genetics and Genomics in Medicine. 9th ed. Elsevier; 2023.",
    "2. Turnpenny P, Ellard S. Emery's Elements of Medical Genetics and Genomics. 16th ed. Elsevier; 2022.",
    "3. Goldman L, Schafer AI. Goldman-Cecil Medicine. 27th ed. International ed. Elsevier; 2024.",
    "4. Loscalzo J et al. Harrison's Principles of Internal Medicine. 22nd ed. McGraw-Hill; 2025.",
    "5. Robbins R, Kumar V. Robbins & Kumar Basic Pathology. 11th ed. Elsevier; 2023.",
    "6. Schäffer AA. Digenic inheritance in medical genetics. J Med Genet. 2013;50:641-652.",
    "7. Marchenko ME. Genetic susceptibility to death from coronary heart disease. NEJM. 1994;330:1041-1046.",
]
for i, r in enumerate(refs):
    add_text(sl, r, 0.5, 1.4 + i*0.72, 12.3, 0.65, size=12, color=C_WHITE)

buf = BytesIO(); prs.save(buf)
with open("/tmp/workspace/genetics-cbd/PPT2_Multifactorial_Malformations.pptx", "wb") as f:
    f.write(buf.getvalue())
print("PPT2 saved OK")

Running Command

rm /tmp/workspace/genetics-cbd/make_ppt2.py /tmp/workspace/genetics-cbd/make_ppt3.py /tmp/workspace/genetics-cbd/make_ppt4.py

Writing File

~/genetics-cbd/make_ppt2.py

"""PPT 2: Multifactorial Congenital Malformations - clean version"""
from pptx import Presentation
from pptx.util import Inches, Pt
from pptx.dml.color import RGBColor
from pptx.enum.text import PP_ALIGN, MSO_ANCHOR
from pptx.enum.shapes import MSO_SHAPE, MSO_CONNECTOR
from io import BytesIO

C_NAVY   = RGBColor(0x0D,0x2B,0x6E)
C_TEAL   = RGBColor(0x00,0x7B,0x8A)
C_LIME   = RGBColor(0x6A,0xB1,0x87)
C_ORANGE = RGBColor(0xE8,0x8B,0x2E)
C_WHITE  = RGBColor(0xFF,0xFF,0xFF)
C_LIGHT  = RGBColor(0xF0,0xF6,0xFB)
C_DARK   = RGBColor(0x1A,0x1A,0x2E)
C_RED    = RGBColor(0xC0,0x39,0x2B)
C_GOLD   = RGBColor(0xF5,0xCB,0x5C)
C_PURPLE = RGBColor(0x7B,0x35,0x7B)
C_GREEN  = RGBColor(0x1A,0x7A,0x4A)

prs = Presentation()
prs.slide_width  = Inches(13.333)
prs.slide_height = Inches(7.5)
BLANK = prs.slide_layouts[6]

def bg(slide, color=C_LIGHT):
    s = slide.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, 0, prs.slide_width, prs.slide_height)
    s.fill.solid(); s.fill.fore_color.rgb = color
    s.line.fill.background(); s.shadow.inherit = False

def hdr(slide, title, subtitle="", col=C_NAVY):
    b = slide.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, 0, prs.slide_width, Inches(1.25))
    b.fill.solid(); b.fill.fore_color.rgb = col
    b.line.fill.background(); b.shadow.inherit = False
    t = slide.shapes.add_textbox(Inches(0.3), Inches(0.05), Inches(12), Inches(0.7))
    p = t.text_frame.paragraphs[0]; p.text = title
    r = p.runs[0]; r.font.size = Pt(28); r.font.bold = True
    r.font.color.rgb = C_WHITE; r.font.name = "Calibri"
    if subtitle:
        t2 = slide.shapes.add_textbox(Inches(0.35), Inches(0.78), Inches(12), Inches(0.45))
        p2 = t2.text_frame.paragraphs[0]; p2.text = subtitle
        r2 = p2.runs[0]; r2.font.size = Pt(15); r2.font.color.rgb = C_GOLD; r2.font.name = "Calibri"

def add_text(slide, text, x, y, w, h, size=13, bold=False, color=C_DARK,
             align=PP_ALIGN.LEFT, italic=False, wrap=True):
    box = slide.shapes.add_textbox(Inches(x), Inches(y), Inches(w), Inches(h))
    tf = box.text_frame; tf.word_wrap = wrap
    p = tf.paragraphs[0]; p.text = text; p.alignment = align
    r = p.runs[0]; r.font.size = Pt(size); r.font.bold = bold
    r.font.color.rgb = color; r.font.name = "Calibri"; r.font.italic = italic

def cbox(slide, text, x, y, w, h, bg_c, tc=C_WHITE, size=12, bold=False):
    s = slide.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                               Inches(x), Inches(y), Inches(w), Inches(h))
    s.fill.solid(); s.fill.fore_color.rgb = bg_c
    s.line.fill.background(); s.shadow.inherit = False
    tf = s.text_frame; tf.word_wrap = True; tf.vertical_anchor = MSO_ANCHOR.MIDDLE
    p = tf.paragraphs[0]; p.text = text; p.alignment = PP_ALIGN.CENTER
    r = p.runs[0]; r.font.size = Pt(size); r.font.color.rgb = tc
    r.font.bold = bold; r.font.name = "Calibri"

def foot(slide, ref):
    ln = slide.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,
                                    Inches(0.3), Inches(7.15), Inches(13), Inches(7.15))
    ln.line.color.rgb = C_TEAL; ln.line.width = Pt(1)
    add_text(slide, ref, 0.3, 7.18, 12.7, 0.3, size=9, italic=True,
             color=RGBColor(0x55, 0x55, 0x55))

# ── TITLE ────────────────────────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl, C_NAVY)
dec = sl.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, Inches(3.8), prs.slide_width, Inches(0.1))
dec.fill.solid(); dec.fill.fore_color.rgb = C_TEAL
dec.line.fill.background(); dec.shadow.inherit = False
dec2 = sl.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, Inches(3.9), prs.slide_width, Inches(0.04))
dec2.fill.solid(); dec2.fill.fore_color.rgb = C_GOLD
dec2.line.fill.background(); dec2.shadow.inherit = False
add_text(sl, "GENETICS CBD", 1, 1.2, 11, 0.6, size=22, color=C_GOLD, align=PP_ALIGN.CENTER)
add_text(sl, "MULTIFACTORIAL CONGENITAL\nMALFORMATIONS",
         0.5, 1.85, 12.3, 1.5, size=40, bold=True, color=C_WHITE, align=PP_ALIGN.CENTER)
add_text(sl, "Definition  |  Neuropsychiatric & Bipolar Disease  |  Coronary Artery Disease  |  Modifier Genes  |  Digenic Inheritance",
         1, 3.6, 11.3, 0.6, size=15, color=C_GOLD, align=PP_ALIGN.CENTER)
add_text(sl, "Sources: Thompson & Thompson Genetics 9th ed. | Emery's Elements of Medical Genetics | Goldman-Cecil Medicine",
         1, 6.8, 11.3, 0.5, size=10, italic=True,
         color=RGBColor(0xAA, 0xBB, 0xCC), align=PP_ALIGN.CENTER)

# ── SLIDE 6: DEFINITION ──────────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "6. Multifactorial Congenital Malformations",
    "Polygenic + environmental threshold model", col=C_TEAL)
add_text(sl,
    "Definition: Conditions caused by interaction of MULTIPLE GENES (polygenic) with ENVIRONMENTAL FACTORS. "
    "No single gene or environmental exposure alone is sufficient. Disease appears only when combined liability exceeds a THRESHOLD.",
    0.3, 1.35, 12.7, 0.65, size=13, color=C_DARK)
add_text(sl, "Threshold Model of Liability", 0.3, 2.1, 5.5, 0.38, size=14, bold=True, color=C_NAVY)
for i, (yw, xo, col) in enumerate([
    (0.22, 1.3, RGBColor(0xD6,0xEA,0xF8)),
    (0.30, 1.0, RGBColor(0xA9,0xCC,0xE3)),
    (0.36, 0.7, RGBColor(0x5D,0xAD,0xE8)),
    (0.30, 1.0, RGBColor(0xA9,0xCC,0xE3)),
    (0.22, 1.3, RGBColor(0xD6,0xEA,0xF8)),
]):
    s = sl.shapes.add_shape(MSO_SHAPE.OVAL, Inches(0.4 + xo), Inches(2.55 + i*0.28),
                            Inches(3.8 - xo*0.5), Inches(yw))
    s.fill.solid(); s.fill.fore_color.rgb = col
    s.line.fill.background(); s.shadow.inherit = False
ln = sl.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,
                              Inches(3.4), Inches(2.5), Inches(3.4), Inches(4.05))
ln.line.color.rgb = C_RED; ln.line.width = Pt(3)
add_text(sl, "THRESHOLD", 3.45, 2.52, 1.8, 0.35, size=11, bold=True, color=C_RED)
add_text(sl, "Normal population", 0.4, 4.1, 2.2, 0.35, size=11, italic=True, color=C_TEAL)
add_text(sl, "Affected", 3.5, 4.1, 1.5, 0.35, size=11, italic=True, color=C_RED)
add_text(sl, "Liability (genes + environment) ->", 0.4, 4.5, 5.0, 0.35, size=11, color=C_DARK)
add_text(sl, "Key Characteristics", 6.1, 1.35, 6.9, 0.38, size=14, bold=True, color=C_NAVY)
chars = [
    "Risk is HIGHER in 1st-degree relatives than the general population",
    "Risk DROPS RAPIDLY with decreasing degree of relationship",
    "Risk INCREASES if multiple family members are affected",
    "Carter Effect: higher risk if proband is the less-commonly affected sex",
    "More severe the malformation, higher the recurrence risk",
    "No single Mendelian pattern -- polygenic + multifactorial",
]
for i, c in enumerate(chars):
    cbox(sl, str(i+1), 6.1, 1.82 + i*0.72, 0.45, 0.55, C_TEAL, size=13, bold=True)
    add_text(sl, c, 6.65, 1.86 + i*0.72, 6.4, 0.52, size=12, color=C_DARK)
add_text(sl, "Common Malformations with Multifactorial Inheritance",
         0.3, 5.02, 5.5, 0.38, size=13, bold=True, color=C_TEAL)
items = [
    ("Congenital heart defects", "4-8 per 1000"),
    ("Neural tube defects", "2-10 per 1000"),
    ("Cleft lip +/- palate", "0.4-1.7 per 1000"),
    ("Pyloric stenosis (males)", "5 per 1000"),
    ("Hip dislocation (females)", "2 per 1000"),
    ("Ventricular septal defect", "1.7 per 1000"),
]
for i, (name, inc) in enumerate(items):
    ci = i % 3; ri = i // 3
    xp = 0.3 + ci * 1.75; yp = 5.48 + ri * 0.72
    cbox(sl, name, xp, yp, 1.6, 0.45, C_NAVY, size=9, bold=True)
    add_text(sl, inc, xp, yp + 0.48, 1.6, 0.28, size=9, color=C_ORANGE, bold=True)
foot(sl, "Thompson & Thompson Genetics 9th ed., p.181-182 | Emery's Elements of Medical Genetics | Robbins & Kumar Basic Pathology")

# ── SLIDE 7: NEUROPSYCHIATRIC / BIPOLAR ──────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "7. Neuropsychiatric Disorders & Bipolar Disease",
    "Schizophrenia and Bipolar Disorder -- complex multifactorial traits", col=C_PURPLE)
cbox(sl, "SCHIZOPHRENIA", 0.3, 1.35, 6.0, 0.52, C_NAVY, size=16, bold=True)
add_text(sl, "Prevalence: 1% worldwide | Onset: late adolescence/young adulthood",
         0.3, 1.92, 6.0, 0.38, size=12, color=C_DARK)
add_text(sl, "Features: disordered thought, emotion, social relationships; delusions; hallucinations",
         0.3, 2.3, 6.0, 0.4, size=12, color=C_DARK)
add_text(sl, "Recurrence Risks in Schizophrenia", 0.3, 2.82, 6.0, 0.35, size=13, bold=True, color=C_TEAL)
risks = [
    ("Child of 2 affected parents", "46%",  C_RED),
    ("Child of 1 affected parent",  "9-16%", C_ORANGE),
    ("Sibling",                     "8-14%", C_ORANGE),
    ("Nephew / niece",              "1-4%",  C_TEAL),
    ("First cousin",                "2-6%",  C_LIME),
]
for i, (rel, risk, col) in enumerate(risks):
    yp = 3.22 + i * 0.5
    cbox(sl, rel,  0.3, yp, 4.2, 0.42, C_LIGHT, tc=C_DARK, size=11)
    cbox(sl, risk, 4.6, yp, 1.6, 0.42, col, size=13, bold=True)
cbox(sl, "MZ twins: 40-60%", 0.3, 5.75, 2.8, 0.48, C_TEAL, size=13, bold=True)
cbox(sl, "DZ twins: 10-16%", 3.2, 5.75, 2.8, 0.48, C_ORANGE, size=13, bold=True)
add_text(sl, "22q11 deletion: 25% lifetime risk of schizophrenia",
         0.3, 6.3, 6.0, 0.38, size=11, italic=True, color=C_DARK)
cbox(sl, "BIPOLAR DISORDER (Manic-Depressive Illness)", 6.5, 1.35, 6.5, 0.52, C_ORANGE, size=14, bold=True, tc=C_DARK)
add_text(sl, "Prevalence: 1-2% worldwide | Heritability: ~70-80% | Cycles of mania and depression",
         6.5, 1.92, 6.5, 0.45, size=12, color=C_DARK)
add_text(sl, "Genetic Evidence", 6.5, 2.5, 6.5, 0.35, size=13, bold=True, color=C_NAVY)
bp = [
    ("MZ concordance",           "40-70%",           C_ORANGE),
    ("DZ concordance",           "15-25%",           C_LIME),
    ("1st-degree relative risk", "~10x general pop", C_RED),
    ("Heritability",             "~70-80%",          C_TEAL),
]
for i, (label, val, col) in enumerate(bp):
    xp = 6.5 + (i % 2) * 3.2; yp = 2.92 + (i // 2) * 0.72
    cbox(sl, label, xp, yp, 2.9, 0.45, col, size=11, bold=True)
    add_text(sl, val, xp + 0.1, yp + 0.48, 2.8, 0.28, size=12, bold=True, color=col)
add_text(sl, "GWAS Loci (Bipolar Disorder)", 6.5, 4.55, 6.5, 0.35, size=13, bold=True, color=C_NAVY)
loci = [
    "CACNA1C -- voltage-gated calcium channel",
    "ANK3 -- ankyrin G, axon initial segment",
    "NCAN -- neurocan ECM glycoprotein",
    "TRANK1 | SYNE1 -- additional risk loci",
    "Overlapping genetic architecture with schizophrenia (cross-disorder genetics)",
]
for i, l in enumerate(loci):
    add_text(sl, "* " + l, 6.5, 4.95 + i * 0.38, 6.5, 0.36, size=11, color=C_DARK)
ge = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                         Inches(0.3), Inches(6.78), Inches(12.7), Inches(0.42))
ge.fill.solid(); ge.fill.fore_color.rgb = RGBColor(0xE8, 0xF4, 0xF8)
ge.line.color.rgb = C_TEAL; ge.line.width = Pt(1); ge.shadow.inherit = False
add_text(sl, "Gene x Environment Triggers: childhood trauma | sleep disruption | cannabis | obstetric complications | urban birth",
         0.4, 6.82, 12.4, 0.35, size=11, color=C_NAVY)
foot(sl, "Thompson & Thompson Genetics 9th ed., p.182-183 | Goldman-Cecil Medicine, International Edition")

# ── SLIDE 8: CORONARY ARTERY DISEASE ─────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "8. Coronary Artery Disease (CAD)",
    "Most common cause of death globally -- complex multifactorial disease", col=C_RED)
add_text(sl, "Genetic Evidence from Twin Studies", 0.3, 1.35, 6.2, 0.38, size=14, bold=True, color=C_NAVY)
for i, h in enumerate(["Twin pair", "Concordance", "Relative risk vs. pop."]):
    cbox(sl, h, 0.3 + i*2.0, 1.82, 1.85, 0.42, C_NAVY, size=11, bold=True)
twin_data = [
    ("Male MZ twins",   "39%", "6-8x"),
    ("Male DZ twins",   "26%", "3x"),
    ("Female MZ twins", "44%", "15x"),
    ("Female DZ twins", "14%", "2.6x"),
]
for i, (pair, conc, rr) in enumerate(twin_data):
    yp = 2.3 + i * 0.5
    for j, (val, bgc, tc) in enumerate([(pair, C_LIGHT, C_DARK),
                                         (conc, C_ORANGE, C_WHITE),
                                         (rr, C_RED, C_WHITE)]):
        cbox(sl, val, 0.3 + j*2.0, yp, 1.85, 0.42, bgc, tc=tc, size=11, bold=(j > 0))
add_text(sl, "Stepwise Pathway -- Genetic Factors", 0.3, 4.62, 6.2, 0.38, size=13, bold=True, color=C_TEAL)
stages = [
    ("Lipid metabolism",     "APOE, LDLR, APOC3, LPA (lipoprotein(a))",     C_TEAL),
    ("Vasoactivity",         "ACE (angiotensin-converting enzyme), AGTR1",   C_ORANGE),
    ("Coagulation",          "Factor V Leiden (R506Q), Prothrombin G20210A", C_RED),
    ("Inflammation",         "IL-6, CRP, TNF-alpha loci",                    C_PURPLE),
    ("Endothelial function", "NOS3 (endothelial nitric oxide synthase)",     C_GREEN),
]
for i, (stage, genes, col) in enumerate(stages):
    yp = 5.05 + i * 0.38
    cbox(sl, stage, 0.3, yp, 2.0, 0.32, col, size=10, bold=True)
    add_text(sl, genes, 2.4, yp + 0.02, 4.1, 0.3, size=10, color=C_DARK)
add_text(sl, "Environmental Risk Factors", 6.6, 1.35, 6.4, 0.38, size=14, bold=True, color=C_NAVY)
for i, e in enumerate(["Diet: saturated fats, trans fats", "Physical inactivity", "Smoking",
                        "Obesity & type 2 diabetes mellitus", "Systemic inflammation"]):
    cbox(sl, e, 6.6, 1.82 + i*0.55, 6.2, 0.45, C_LIGHT, tc=C_DARK, size=12)
add_text(sl, "Key GWAS Findings", 6.6, 4.65, 6.4, 0.38, size=14, bold=True, color=C_TEAL)
for i, g in enumerate([
    "9p21.3 locus -- strongest replicated CAD locus (CDKN2A/CDKN2B region)",
    ">300 independent loci identified genome-wide",
    "Polygenic Risk Scores (PRS) show growing clinical utility",
    "Familial Hypercholesterolaemia: LDLR mutations (AD) markedly raise LDL",
    "Intermediate traits (HTN, DM, obesity) each have additional genetic architecture",
]):
    add_text(sl, "* " + g, 6.6, 5.1 + i*0.42, 6.4, 0.4, size=11, color=C_DARK)
foot(sl, "Thompson & Thompson Genetics 9th ed., p.183-184 | Goldman-Cecil Medicine")

# ── SLIDE 9: MODIFIER GENES ──────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "9. Modifier Genes",
    "Secondary gene loci that modulate disease severity without causing the disease", col=C_TEAL)
add_text(sl,
    "Definition: Modifier genes are genes whose allelic variants affect the EXPRESSION, SEVERITY, or PHENOTYPE "
    "of a disease caused by mutations in a DIFFERENT primary gene. They do not cause the disease themselves.",
    0.3, 1.35, 12.7, 0.65, size=13, color=C_DARK)
cbox(sl, "CLASSIC EXAMPLE: CYSTIC FIBROSIS (CF)",
     0.3, 2.1, 12.7, 0.52, C_NAVY, size=15, bold=True)
add_text(sl, "Primary gene: CFTR  |  Variable phenotype NOT fully explained by CFTR genotype alone",
         0.3, 2.68, 12.7, 0.38, size=13, color=C_DARK)
for i, (name, desc, effect, col) in enumerate([
    ("MBL2\n(Mannose-Binding Lectin 2)",
     "Innate immunity plasma protein -- binds pathogens\n"
     "Low MBL2 alleles -> reduced innate immunity -> worse Pseudomonas containment in CF",
     "Low MBL2 alleles -> WORSE pulmonary outcome in CF", C_TEAL),
    ("TGFB1\n(Transforming Growth Factor-b)",
     "High TGFb-producing alleles -> increased lung fibrosis/scarring\n"
     "after chronic neutrophilic inflammation in CF airways",
     "High TGFB1 alleles -> WORSE FEV1 decline in CF", C_ORANGE),
]):
    xp = 0.3 + i * 6.4
    cbox(sl, name, xp, 3.18, 2.3, 0.85, col, size=12, bold=True)
    add_text(sl, desc, xp + 2.4, 3.22, 3.8, 0.8, size=11, color=C_DARK)
    cbox(sl, effect, xp, 4.1, 6.2, 0.48, C_LIGHT, tc=col, size=11, bold=True)
note = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                           Inches(0.3), Inches(4.68), Inches(12.7), Inches(0.52))
note.fill.solid(); note.fill.fore_color.rgb = RGBColor(0xE8, 0xF4, 0xF8)
note.line.color.rgb = C_TEAL; note.line.width = Pt(1); note.shadow.inherit = False
add_text(sl,
    "CF Lung Disease Heritability: ~50% (from MZ vs DZ twins in CF patients) -- "
    "INDEPENDENT of CFTR allele; confirms 50% of lung disease severity is due to genes OTHER than CFTR",
    0.4, 4.73, 12.4, 0.42, size=11, bold=True, color=C_NAVY)
add_text(sl, "Further Examples of Modifier Genes", 0.3, 5.32, 12.7, 0.38, size=14, bold=True, color=C_NAVY)
for i, h in enumerate(["Primary Disease", "Modifier Gene", "Effect on Phenotype"]):
    cbox(sl, h, 0.3 + i*4.2, 5.75, 4.0, 0.38, C_NAVY, size=11, bold=True)
for i, (pd, mg, eff) in enumerate([
    ("Cystic fibrosis",                "MBL2 / TGFB1",                  "Pulmonary disease severity"),
    ("Sickle cell disease",            "BCL11A, HBG (fetal Hb regs)",   "Severity of vaso-occlusive crises"),
    ("Familial hypercholesterolaemia", "APOE genotype",                  "Cardiovascular disease severity"),
    ("Huntington disease",             "MSH3 (DNA mismatch repair)",     "Age of onset modulation"),
]):
    yp = 6.18 + i * 0.3
    for j, (val, bgc) in enumerate(zip([pd, mg, eff],
                                        [C_LIGHT, RGBColor(0xD6,0xEA,0xF8), RGBColor(0xD5,0xF5,0xE3)])):
        cbox(sl, val, 0.3 + j*4.2, yp, 4.0, 0.28, bgc, tc=C_DARK, size=10)
foot(sl, "Thompson & Thompson Genetics 9th ed., p.185 | Goldman-Cecil Medicine | Harrison's Principles 22E")

# ── SLIDE 10: DIGENIC INHERITANCE ────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "10. Digenic Inheritance",
    "Simplest multigenic inheritance -- disease requires mutations at TWO different loci", col=C_NAVY)
add_text(sl,
    "Definition: Disease manifests ONLY when pathogenic variants at TWO DIFFERENT GENE LOCI are combined. "
    "Heterozygous variants at either locus alone are insufficient -- only the co-occurrence of both causes the phenotype.",
    0.3, 1.35, 12.7, 0.65, size=13, color=C_DARK)
cbox(sl, "Gene A\n(Heterozygous)\nCarrier -- unaffected",
     0.5, 2.15, 2.8, 1.05, C_TEAL, size=12, bold=True)
add_text(sl, "+", 3.4, 2.45, 0.5, 0.55, size=24, bold=True, color=C_DARK, align=PP_ALIGN.CENTER)
cbox(sl, "Gene B\n(Heterozygous)\nCarrier -- unaffected",
     4.0, 2.15, 2.8, 1.05, C_ORANGE, size=12, bold=True)
add_text(sl, "=", 6.9, 2.45, 0.5, 0.55, size=24, bold=True, color=C_DARK, align=PP_ALIGN.CENTER)
cbox(sl, "DISEASE\n(Both mutations present together)",
     7.5, 2.15, 2.8, 1.05, C_RED, size=12, bold=True)
cbox(sl, "Gene A alone -> NORMAL",   0.5, 3.35, 2.8, 0.38, C_LIGHT, tc=C_TEAL, size=11, bold=True)
cbox(sl, "Gene B alone -> NORMAL",   4.0, 3.35, 2.8, 0.38, C_LIGHT, tc=C_ORANGE, size=11, bold=True)
cbox(sl, "Both together -> DISEASE", 7.5, 3.35, 2.8, 0.38, C_RED, size=11, bold=True)
add_text(sl, "Key Characteristics", 0.3, 3.95, 5.5, 0.38, size=14, bold=True, color=C_NAVY)
for i, c in enumerate([
    "Neither mutation alone causes disease",
    "Parents carrying one mutation each are UNAFFECTED",
    "Child inheriting BOTH mutations has 25% risk (if parents carry at different loci)",
    "Appears sporadic/recessive-like in pedigrees",
    "AR = 2 mutations SAME locus; Digenic = 1 mutation at EACH of 2 DIFFERENT loci",
]):
    cbox(sl, str(i+1), 0.3, 4.38 + i*0.5, 0.42, 0.42, C_TEAL, size=13, bold=True)
    add_text(sl, c, 0.82, 4.4 + i*0.5, 5.0, 0.44, size=11, color=C_DARK)
add_text(sl, "Clinical Examples", 6.4, 3.95, 6.6, 0.38, size=14, bold=True, color=C_NAVY)
for i, (name, col, desc) in enumerate([
    ("Digenic Retinitis Pigmentosa", C_RED,
     "ROM1 + PRPH2 (peripherin)\nEither alone = normal; both together = RP"),
    ("Waardenburg Syndrome Type III", C_PURPLE,
     "PAX3 + MITF heterozygosity"),
    ("Bardet-Biedl Syndrome", C_ORANGE,
     "Mutations at 2+ BBS loci (oligogenic/triallelic)"),
    ("Hereditary Deafness (GJB2/GJB6)", C_TEAL,
     "Connexin 26 + Connexin 30 -- combined deletion/mutation -> deafness"),
]):
    yp = 4.42 + i * 0.65
    cbox(sl, name, 6.4, yp, 6.4, 0.42, col, size=11, bold=True)
    add_text(sl, desc, 6.5, yp + 0.45, 6.2, 0.4, size=10, color=C_DARK)
cs = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                         Inches(0.3), Inches(6.82), Inches(12.7), Inches(0.42))
cs.fill.solid(); cs.fill.fore_color.rgb = C_NAVY
cs.line.fill.background(); cs.shadow.inherit = False
add_text(sl,
    "Clinical Significance: Explains sporadic cases in single-carrier families | "
    "Critical for genomic sequencing interpretation -- VUS at two loci may act diigenically",
    0.4, 6.87, 12.4, 0.35, size=11, color=C_WHITE)
foot(sl, "Emery's Elements of Medical Genetics (citing Schaffer, J Med Genet 2013) | Thompson & Thompson Genetics 9th ed.")

# ── REFERENCES ───────────────────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl, C_NAVY)
hdr(sl, "References", "Multifactorial Congenital Malformations", col=C_TEAL)
for i, r in enumerate([
    "1. Thompson MW et al. Thompson & Thompson Genetics and Genomics in Medicine. 9th ed. Elsevier; 2023.",
    "2. Turnpenny P, Ellard S. Emery's Elements of Medical Genetics and Genomics. 16th ed. Elsevier; 2022.",
    "3. Goldman L, Schafer AI. Goldman-Cecil Medicine. 27th ed. International ed. Elsevier; 2024.",
    "4. Loscalzo J et al. Harrison's Principles of Internal Medicine. 22nd ed. McGraw-Hill; 2025.",
    "5. Robbins R, Kumar V. Robbins & Kumar Basic Pathology. 11th ed. Elsevier; 2023.",
    "6. Schaffer AA. Digenic inheritance in medical genetics. J Med Genet. 2013;50:641-652.",
    "7. Marchenko ME. Genetic susceptibility to death from coronary heart disease. NEJM. 1994;330:1041.",
]):
    add_text(sl, r, 0.5, 1.4 + i*0.72, 12.3, 0.65, size=12, color=C_WHITE)

buf = BytesIO(); prs.save(buf)
with open("/tmp/workspace/genetics-cbd/PPT2_Multifactorial_Malformations.pptx", "wb") as f:
    f.write(buf.getvalue())
print("PPT2 saved OK")

Writing File

~/genetics-cbd/make_ppt3.py

"""PPT 3: Autosomal Recessive Inheritance"""
from pptx import Presentation
from pptx.util import Inches, Pt
from pptx.dml.color import RGBColor
from pptx.enum.text import PP_ALIGN, MSO_ANCHOR
from pptx.enum.shapes import MSO_SHAPE, MSO_CONNECTOR
from io import BytesIO

C_NAVY   = RGBColor(0x0D,0x2B,0x6E)
C_TEAL   = RGBColor(0x00,0x7B,0x8A)
C_LIME   = RGBColor(0x6A,0xB1,0x87)
C_ORANGE = RGBColor(0xE8,0x8B,0x2E)
C_WHITE  = RGBColor(0xFF,0xFF,0xFF)
C_LIGHT  = RGBColor(0xF0,0xF6,0xFB)
C_DARK   = RGBColor(0x1A,0x1A,0x2E)
C_RED    = RGBColor(0xC0,0x39,0x2B)
C_GOLD   = RGBColor(0xF5,0xCB,0x5C)
C_PURPLE = RGBColor(0x7B,0x35,0x7B)
C_GREEN  = RGBColor(0x1A,0x7A,0x4A)

prs = Presentation()
prs.slide_width  = Inches(13.333)
prs.slide_height = Inches(7.5)
BLANK = prs.slide_layouts[6]

def bg(slide, color=C_LIGHT):
    s = slide.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, 0, prs.slide_width, prs.slide_height)
    s.fill.solid(); s.fill.fore_color.rgb = color
    s.line.fill.background(); s.shadow.inherit = False

def hdr(slide, title, subtitle="", col=C_NAVY):
    b = slide.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, 0, prs.slide_width, Inches(1.25))
    b.fill.solid(); b.fill.fore_color.rgb = col
    b.line.fill.background(); b.shadow.inherit = False
    t = slide.shapes.add_textbox(Inches(0.3), Inches(0.05), Inches(12), Inches(0.7))
    p = t.text_frame.paragraphs[0]; p.text = title
    r = p.runs[0]; r.font.size = Pt(28); r.font.bold = True
    r.font.color.rgb = C_WHITE; r.font.name = "Calibri"
    if subtitle:
        t2 = slide.shapes.add_textbox(Inches(0.35), Inches(0.78), Inches(12), Inches(0.45))
        p2 = t2.text_frame.paragraphs[0]; p2.text = subtitle
        r2 = p2.runs[0]; r2.font.size = Pt(15); r2.font.color.rgb = C_GOLD; r2.font.name = "Calibri"

def add_text(slide, text, x, y, w, h, size=13, bold=False, color=C_DARK,
             align=PP_ALIGN.LEFT, italic=False, wrap=True):
    box = slide.shapes.add_textbox(Inches(x), Inches(y), Inches(w), Inches(h))
    tf = box.text_frame; tf.word_wrap = wrap
    p = tf.paragraphs[0]; p.text = text; p.alignment = align
    r = p.runs[0]; r.font.size = Pt(size); r.font.bold = bold
    r.font.color.rgb = color; r.font.name = "Calibri"; r.font.italic = italic

def cbox(slide, text, x, y, w, h, bg_c, tc=C_WHITE, size=12, bold=False):
    s = slide.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                               Inches(x), Inches(y), Inches(w), Inches(h))
    s.fill.solid(); s.fill.fore_color.rgb = bg_c
    s.line.fill.background(); s.shadow.inherit = False
    tf = s.text_frame; tf.word_wrap = True; tf.vertical_anchor = MSO_ANCHOR.MIDDLE
    p = tf.paragraphs[0]; p.text = text; p.alignment = PP_ALIGN.CENTER
    r = p.runs[0]; r.font.size = Pt(size); r.font.color.rgb = tc
    r.font.bold = bold; r.font.name = "Calibri"

def foot(slide, ref):
    ln = slide.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,
                                    Inches(0.3), Inches(7.15), Inches(13), Inches(7.15))
    ln.line.color.rgb = C_TEAL; ln.line.width = Pt(1)
    add_text(slide, ref, 0.3, 7.18, 12.7, 0.3, size=9, italic=True,
             color=RGBColor(0x55, 0x55, 0x55))

# ── TITLE ─────────────────────────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl, C_NAVY)
dec = sl.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, Inches(3.8), prs.slide_width, Inches(0.1))
dec.fill.solid(); dec.fill.fore_color.rgb = C_TEAL
dec.line.fill.background(); dec.shadow.inherit = False
dec2 = sl.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, Inches(3.9), prs.slide_width, Inches(0.04))
dec2.fill.solid(); dec2.fill.fore_color.rgb = C_GOLD
dec2.line.fill.background(); dec2.shadow.inherit = False
add_text(sl, "GENETICS CBD", 1, 1.2, 11, 0.6, size=22, color=C_GOLD, align=PP_ALIGN.CENTER)
add_text(sl, "AUTOSOMAL RECESSIVE\nINHERITANCE",
         0.5, 1.9, 12.3, 1.5, size=44, bold=True, color=C_WHITE, align=PP_ALIGN.CENTER)
add_text(sl, "Definition  |  Cystic Fibrosis  |  Marfan Syndrome  |  Phenylketonuria  |  CF Phenotypic Features",
         1, 3.65, 11.3, 0.6, size=15, color=C_GOLD, align=PP_ALIGN.CENTER)
add_text(sl, "Sources: Goldman-Cecil Medicine | Harrison's 22E | Thompson & Thompson Genetics 9th ed.",
         1, 6.8, 11.3, 0.5, size=10, italic=True,
         color=RGBColor(0xAA, 0xBB, 0xCC), align=PP_ALIGN.CENTER)

# ── SLIDE 11: AR DEFINITION ───────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "11. Autosomal Recessive Inheritance",
    "Two pathogenic alleles required; heterozygotes (carriers) are unaffected", col=C_NAVY)

# Pedigree cross diagram
add_text(sl, "Carrier x Carrier Cross  (Aa x Aa)", 0.3, 1.38, 5.5, 0.38, size=14, bold=True, color=C_NAVY)
cbox(sl, "Father\n(Carrier Aa)", 0.4, 1.85, 1.8, 0.8, C_TEAL, size=12, bold=True)
add_text(sl, "x", 2.25, 2.1, 0.4, 0.4, size=20, bold=True, color=C_DARK, align=PP_ALIGN.CENTER)
cbox(sl, "Mother\n(Carrier Aa)", 2.65, 1.85, 1.8, 0.8, C_TEAL, size=12, bold=True)
ln2 = sl.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,
                               Inches(2.55), Inches(2.65), Inches(2.55), Inches(3.1))
ln2.line.color.rgb = C_DARK; ln2.line.width = Pt(2)
offspring = [("AA 25%\nNormal", C_LIME, C_DARK), ("Aa 50%\nCarrier", C_TEAL, C_WHITE),
             ("Aa 50%\nCarrier", C_TEAL, C_WHITE), ("aa 25%\nAFFECTED", C_RED, C_WHITE)]
for i, (lbl, col, tc) in enumerate(offspring):
    cbox(sl, lbl, 0.3 + i*1.28, 3.15, 1.18, 0.85, col, tc=tc, size=10, bold=True)

add_text(sl, "Rules of AR Inheritance", 0.3, 4.18, 5.5, 0.38, size=14, bold=True, color=C_TEAL)
for i, r in enumerate([
    "1. Both sexes equally affected (autosomal gene)",
    "2. Parents are typically unaffected carriers (Aa x Aa)",
    "3. Horizontal pattern: affected siblings in one generation",
    "4. Consanguinity increases risk (alleles identical by descent)",
    "5. No male-to-male (or male-to-female) vertical pattern",
    "6. Compound heterozygosity: two different pathogenic alleles at same locus",
]):
    add_text(sl, r, 0.3, 4.6 + i*0.38, 5.3, 0.36, size=11, color=C_DARK)
hw = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                         Inches(0.3), Inches(6.9), Inches(5.5), Inches(0.45))
hw.fill.solid(); hw.fill.fore_color.rgb = RGBColor(0xD5,0xF5,0xE3)
hw.line.color.rgb = C_GREEN; hw.line.width = Pt(1.5); hw.shadow.inherit = False
add_text(sl, "Hardy-Weinberg: If disease freq = q^2 (CF: 1/2500), q = 1/50, carrier freq 2pq ~= 1/25 (4%)",
         0.4, 6.95, 5.3, 0.37, size=11, color=C_DARK)

# Right panel: comparison table
add_text(sl, "Comparison: AR vs AD vs X-linked Recessive", 5.9, 1.38, 7.1, 0.38, size=14, bold=True, color=C_NAVY)
hcols = ["Feature", "AR", "AD", "XLR"]
col_widths = [2.8, 1.4, 1.4, 1.4]
x_starts = [5.9, 8.75, 10.2, 11.65]
for i, (h, xp, cw) in enumerate(zip(hcols, x_starts, col_widths)):
    cbox(sl, h, xp, 1.82, cw, 0.42, C_NAVY, size=11, bold=True)
for i, (feat, ar, ad, xlr) in enumerate([
    ("Both sexes",      "Equal",           "Equal",       "Males mainly"),
    ("Carrier parents", "Unaffected",      "--",          "Unaffected females"),
    ("Skip generations","Yes",             "No",          "Yes"),
    ("Consanguinity",   "Increases risk",  "No effect",   "No effect"),
    ("M->son transmit.","Possible",        "Possible",    "NEVER"),
]):
    yp = 2.3 + i * 0.58
    for j, (val, xp, cw) in enumerate(zip([feat, ar, ad, xlr], x_starts, col_widths)):
        bgc = [C_LIGHT, RGBColor(0xD6,0xEA,0xF8), RGBColor(0xFD,0xED,0xEC), RGBColor(0xD5,0xF5,0xE3)][j]
        cbox(sl, val, xp, yp, cw, 0.5, bgc, tc=C_DARK, size=11)

add_text(sl, "Common AR Diseases", 5.9, 5.35, 7.1, 0.38, size=13, bold=True, color=C_TEAL)
for i, d in enumerate(["Cystic Fibrosis (CFTR, chr 7q31)", "Phenylketonuria (PAH, chr 12q23)",
                        "Sickle Cell Disease (HBB, chr 11p15)", "Thalassaemia (HBA/HBB)",
                        "Wilson's Disease (ATP7B)", "Haemochromatosis (HFE, C282Y)",
                        "Spinal Muscular Atrophy (SMN1)"]):
    add_text(sl, "* " + d, 5.9, 5.75 + i*0.32, 7.1, 0.3, size=11, color=C_DARK)

foot(sl, "Goldman-Cecil Medicine | Basic Medical Biochemistry 6th ed. | Dermatology 2-Volume Set 5th ed.")

# ── SLIDE 12: CYSTIC FIBROSIS ─────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "12. Cystic Fibrosis",
    "AR | CFTR gene, Chr 7q31.2 | Most common life-shortening AR disease in White populations", col=C_TEAL)

add_text(sl, "CFTR Mutation Classes", 0.3, 1.35, 5.0, 0.4, size=14, bold=True, color=C_NAVY)
for i, (cls, defect, muts, col) in enumerate([
    ("I",  "No synthesis (stop codon)",       "W1282X, G542X",        C_RED),
    ("II", "Protein misfolding/degradation",  "F508del (70%!), N1303K", C_ORANGE),
    ("III","Defective channel gating",        "G551D, G551S",          C_PURPLE),
    ("IV", "Reduced Cl- conductance",         "R117H, R334W",          C_TEAL),
    ("V",  "Reduced transcription/splicing",  "3849+10kbC->T",         C_GREEN),
    ("VI", "Unstable protein",                "4326delTC",             RGBColor(0x2E,0x86,0xAB)),
]):
    cbox(sl, "Class " + cls, 0.3, 1.82 + i*0.62, 1.0, 0.52, col, size=12, bold=True)
    add_text(sl, defect, 1.4, 1.86 + i*0.62, 1.9, 0.5, size=11, color=C_DARK)
    add_text(sl, muts, 3.35, 1.86 + i*0.62, 1.9, 0.5, size=10, color=col, bold=True)

ep = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                         Inches(0.3), Inches(5.72), Inches(4.85), Inches(0.7))
ep.fill.solid(); ep.fill.fore_color.rgb = RGBColor(0xE8,0xF4,0xF8)
ep.line.color.rgb = C_TEAL; ep.line.width = Pt(1); ep.shadow.inherit = False
add_text(sl, "Epidemiology: Northern Europe/Americas 1:2500-3000 | USA 1:10,000 | Hispanic 1:7,000 | African American 1:12,000",
         0.4, 5.78, 4.65, 0.58, size=10, color=C_DARK)

add_text(sl, "Pathophysiology by Organ System", 5.4, 1.35, 7.6, 0.4, size=14, bold=True, color=C_NAVY)
for i, (organ, desc, col) in enumerate([
    ("LUNGS (~90% mortality)",
     "Reduced Cl-/HCO3- secretion -> airway dehydration -> mucus plugging -> chronic Pseudomonas -> bronchiectasis", C_RED),
    ("SWEAT GLANDS",
     "Sweat Cl- >=60 mEq/L (DIAGNOSTIC) | Salt wasting | Hyponatremic alkalosis | 'Salty tasting skin'", C_TEAL),
    ("PANCREAS",
     "Exocrine insufficiency -> steatorrhea, fat-soluble vitamin deficiency | CF-related diabetes (CFRD)", C_ORANGE),
    ("LIVER & BILIARY",
     "Biliary canalicular obstruction -> cirrhosis (5%) | Portal hypertension | Gallstones (30%)", RGBColor(0x5D,0x6D,0x7E)),
    ("GI TRACT",
     "Meconium ileus (15-20% neonates) | DIOS in older patients | Rectal prolapse | GERD", C_PURPLE),
    ("REPRODUCTIVE",
     "Males: CBAVD -> obstructive azoospermia -> infertility >95% | Females: thick cervical mucus -> reduced fertility", C_GREEN),
]):
    yp = 1.82 + i*0.82
    cbox(sl, organ, 5.4, yp, 2.0, 0.65, col, size=10, bold=True)
    add_text(sl, desc, 7.5, yp + 0.06, 5.5, 0.62, size=10, color=C_DARK)

foot(sl, "Goldman-Cecil Medicine p.3231-3290 | Harrison's Principles of Internal Medicine 22E | Medical Physiology")

# ── SLIDE 13: MARFAN SYNDROME ─────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "13. Marfan Syndrome",
    "Autosomal DOMINANT | FBN1 gene, Chr 15q21.1 | Connective tissue disorder (included for comparison)",
    col=C_ORANGE)

note = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                           Inches(0.3), Inches(1.35), Inches(12.7), Inches(0.45))
note.fill.solid(); note.fill.fore_color.rgb = RGBColor(0xFE,0xF9,0xE7)
note.line.color.rgb = C_ORANGE; note.line.width = Pt(2); note.shadow.inherit = False
add_text(sl, "NOTE: Marfan syndrome is AUTOSOMAL DOMINANT -- included here for differential comparison with AR connective tissue disorders",
         0.4, 1.4, 12.4, 0.37, size=11, bold=True, color=RGBColor(0x78,0x3F,0x04))

cbox(sl, "Gene: FBN1 (Fibrillin-1)  |  Chromosome 15q21.1\nAutosomal Dominant  |  ~75% inherited, ~25% de novo",
     0.3, 1.88, 4.5, 0.85, C_NAVY, size=12, bold=True)

add_text(sl, "Pathophysiology", 0.3, 2.88, 4.5, 0.38, size=14, bold=True, color=C_TEAL)
for i, p in enumerate([
    "Fibrillin-1: major structural component of extracellular microfibrils",
    "Microfibrils provide integrity to: aortic wall, lens zonules, ligaments, lung airways, spinal dura",
    "Mutant FBN1 -> weakened microfibrils + excess TGF-b signaling",
    "Excess TGF-b -> progressive aortic wall degradation and dilatation",
]):
    add_text(sl, "* " + p, 0.3, 3.3 + i*0.45, 4.5, 0.43, size=11, color=C_DARK)

dbox = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                           Inches(0.3), Inches(5.28), Inches(4.5), Inches(1.38))
dbox.fill.solid(); dbox.fill.fore_color.rgb = RGBColor(0xD5,0xF5,0xE3)
dbox.line.color.rgb = C_GREEN; dbox.line.width = Pt(1.5); dbox.shadow.inherit = False
add_text(sl, "Ghent Criteria 2010 (any one):", 0.4, 5.33, 4.3, 0.35, size=12, bold=True, color=C_GREEN)
for i, cr in enumerate([
    "Aortic root dilatation (Z>=2.0) + ectopia lentis",
    "Aortic root dilatation + FBN1 pathogenic variant",
    "Ectopia lentis + FBN1 variant + aortic disease",
    "Systemic score >=7 + aortic disease",
]):
    add_text(sl, "* " + cr, 0.4, 5.72 + i*0.23, 4.3, 0.22, size=10, color=C_DARK)

add_text(sl, "Cardinal Clinical Features", 5.0, 1.38, 8.0, 0.38, size=14, bold=True, color=C_NAVY)
for i, (sys_name, col, items) in enumerate([
    ("CARDIOVASCULAR (Most Dangerous)", C_RED,
     ["Aortic root dilatation/aneurysm (Z>=2.0)",
      "Aortic dissection (Type A -- emergency)",
      "Mitral valve prolapse +/- regurgitation",
      "Pulmonary artery dilatation"]),
    ("OCULAR", C_TEAL,
     ["Ectopia lentis (upward subluxation -- 50-80%)",
      "High myopia",
      "Retinal detachment risk",
      "Glaucoma, cataracts"]),
    ("SKELETAL", C_ORANGE,
     ["Tall stature; dolichostenomelia (long limbs)",
      "Arachnodactyly (wrist & thumb signs +ve)",
      "Pectus excavatum/carinatum",
      "Scoliosis | Dural ectasia | Flat feet"]),
]):
    xp = 5.0 + i * 2.75
    cbox(sl, sys_name, xp, 1.85, 2.5, 0.62, col, size=10, bold=True)
    for j, item in enumerate(items):
        add_text(sl, "* " + item, xp, 2.52 + j*0.46, 2.5, 0.42, size=10, color=C_DARK)

mbox = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                           Inches(5.0), Inches(5.55), Inches(8.0), Inches(1.1))
mbox.fill.solid(); mbox.fill.fore_color.rgb = C_NAVY
mbox.line.fill.background(); mbox.shadow.inherit = False
add_text(sl, "Management", 5.1, 5.6, 2.0, 0.35, size=12, bold=True, color=C_GOLD)
add_text(sl, "* Beta-blockers (atenolol) or losartan (anti-TGF-b) to slow aortic dilatation\n"
             "* Elective aortic root repair when diameter reaches 4.5-5.0 cm\n"
             "* Annual echocardiography  |  Restrict contact sports & high-intensity exercise",
         5.1, 5.95, 7.8, 0.65, size=11, color=C_WHITE)

foot(sl, "GeneReviews NBK1335 | Medscape | Emery's Elements of Medical Genetics | Thompson & Thompson Genetics 9th ed.")

# ── SLIDE 14: PHENYLKETONURIA ─────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "14. Phenylketonuria (PKU)",
    "AR | PAH gene, Chr 12q23.2 | Inborn error of phenylalanine metabolism", col=C_PURPLE)

cbox(sl, "Gene: PAH (Phenylalanine Hydroxylase)\nChr 12q23.2  |  90 kb  |  13 exons\nAR -- homozygous or compound heterozygous",
     0.3, 1.38, 4.5, 0.95, C_PURPLE, size=12, bold=True)

add_text(sl, "Biochemical Pathway", 0.3, 2.45, 4.5, 0.38, size=13, bold=True, color=C_NAVY)
cbox(sl, "Phenylalanine\n(dietary)", 0.3, 2.9, 2.0, 0.65, C_TEAL, size=12, bold=True)
ln3 = sl.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,
                               Inches(2.3), Inches(3.22), Inches(2.7), Inches(3.22))
ln3.line.color.rgb = C_GREEN; ln3.line.width = Pt(3)
cbox(sl, "PAH + BH4\n(cofactor)", 2.7, 2.9, 1.6, 0.65, C_GREEN, size=11, bold=True)
ln4 = sl.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,
                               Inches(4.3), Inches(3.22), Inches(4.65), Inches(3.22))
ln4.line.color.rgb = C_GREEN; ln4.line.width = Pt(3)
cbox(sl, "Tyrosine", 4.65, 2.9, 1.4, 0.65, C_LIME, size=12, bold=True, tc=C_DARK)
x2 = sl.shapes.add_shape(MSO_SHAPE.OVAL, Inches(2.72), Inches(2.62), Inches(0.38), Inches(0.38))
x2.fill.solid(); x2.fill.fore_color.rgb = C_RED; x2.line.fill.background(); x2.shadow.inherit = False
tf2 = x2.text_frame; tf2.vertical_anchor = MSO_ANCHOR.MIDDLE
p2 = tf2.paragraphs[0]; p2.text = "X"; p2.alignment = PP_ALIGN.CENTER
r2 = p2.runs[0]; r2.font.size = Pt(12); r2.font.color.rgb = C_WHITE; r2.font.bold = True
cbox(sl, "PAH absent/deficient -> Phe accumulates -> toxic metabolites\n(phenylpyruvate, phenylacetate, phenyllactate)",
     0.3, 3.65, 4.5, 0.65, C_RED, size=11, bold=True)

add_text(sl, "Clinical Phenotypes (untreated)", 0.3, 4.42, 4.5, 0.38, size=13, bold=True, color=C_TEAL)
for i, (ptype, phe, iq, col) in enumerate([
    ("Classic PKU",  ">1200 umol/L",  "Severe ID (IQ<50)",    C_RED),
    ("Moderate PKU", "600-1200",       "Moderate ID",          C_ORANGE),
    ("Mild PKU",     "360-600",        "Mild cognitive effect", C_ORANGE),
    ("Benign hyperphe.", "<360",       "Minimal/none",         C_LIME),
]):
    cbox(sl, ptype, 0.3, 4.85 + i*0.44, 1.8, 0.38, col, size=10, bold=True)
    add_text(sl, "Phe: " + phe, 2.15, 4.87 + i*0.44, 1.4, 0.35, size=10, color=C_DARK)
    add_text(sl, iq, 3.6, 4.87 + i*0.44, 1.1, 0.35, size=10, color=col, bold=True)

ep2 = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                          Inches(0.3), Inches(6.72), Inches(4.5), Inches(0.5))
ep2.fill.solid(); ep2.fill.fore_color.rgb = RGBColor(0xE8,0xF4,0xF8)
ep2.line.color.rgb = C_TEAL; ep2.line.width = Pt(1); ep2.shadow.inherit = False
add_text(sl, "Prevalence: ~1:24,000 globally | Turkey highest (~38:100,000) | US ~1:10,000-15,000",
         0.4, 6.77, 4.3, 0.4, size=11, color=C_DARK)

add_text(sl, "Clinical Features (untreated)", 5.1, 1.38, 8.0, 0.38, size=14, bold=True, color=C_NAVY)
for i, f in enumerate([
    "Profound intellectual disability (IQ <50)",
    "Epilepsy / seizures",
    "Acquired microcephaly",
    "Behavioral disorders (hyperactivity, autism-like)",
    "Generalized hypopigmentation: blue eyes, fair hair, fair skin (reduced tyrosine -> reduced melanin)",
    "Eczema",
    "Mousy/musty odor (phenylacetate in urine and sweat)",
]):
    cbox(sl, str(i+1), 5.1, 1.82 + i*0.48, 0.4, 0.4, C_PURPLE, size=12, bold=True)
    add_text(sl, f, 5.6, 1.84 + i*0.48, 7.3, 0.42, size=11, color=C_DARK)

add_text(sl, "Treatment", 5.1, 5.42, 8.0, 0.38, size=14, bold=True, color=C_TEAL)
for i, (name, desc, col) in enumerate([
    ("Low-Phe diet (lifelong)", "Restrict proteins; phenylalanine-free amino acid formula", C_TEAL),
    ("Sapropterin (Kuvan)",     "BH4 analog -- effective in ~30-50% (BH4-responsive phenotypes)", C_ORANGE),
    ("Pegvaliase",              "PEGylated PAL enzyme -- for adults with classic PKU poorly controlled", C_PURPLE),
    ("Newborn screening",       "MS/MS on heel-prick blood spot day 2-5 | Early treatment = normal IQ", C_GREEN),
]):
    cbox(sl, name, 5.1, 5.85 + i*0.38, 2.4, 0.32, col, size=10, bold=True)
    add_text(sl, desc, 7.6, 5.87 + i*0.38, 5.4, 0.32, size=10, color=C_DARK)

foot(sl, "Goldman-Cecil Medicine | Basic Medical Biochemistry 6th ed. | PMC9295449 (PKU genetics review)")

# ── SLIDE 15: MAJOR PHENOTYPIC FEATURES OF CF ────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "15. Major Phenotypic Features: Cystic Fibrosis",
    "Multisystem disease -- CFTR dysfunction affects every exocrine gland", col=C_TEAL)

for i, (name, desc, col) in enumerate([
    ("PULMONARY\n~90% mortality",
     "Chronic cough | Bronchiectasis | Chronic Pseudomonas/Staph infection\nHemoptysis | Respiratory failure | Cor pulmonale | Pneumothorax",
     C_RED),
    ("SWEAT\nGLANDS",
     "Cl- >=60 mEq/L (DIAGNOSTIC) | Salt wasting\nHyponatremic alkalosis | 'Salty tasting skin'",
     C_TEAL),
    ("PANCREAS",
     "Exocrine insufficiency -> steatorrhea\nFat-soluble vitamin deficiency (A,D,E,K)\nCFRD (CF-related diabetes) in ~50% by age 50",
     C_ORANGE),
    ("LIVER &\nBILIARY",
     "Biliary obstruction -> focal cirrhosis (5-10%)\nPortal hypertension | Gallstones (30%)",
     RGBColor(0x5D,0x6D,0x7E)),
    ("GI TRACT",
     "Meconium ileus (15-20% neonates)\nDIOS in older patients\nRectal prolapse | GERD",
     C_PURPLE),
    ("REPRODUCTIVE",
     "Males: CBAVD -> obstructive azoospermia -> infertility >95%\nFemales: thick cervical mucus -> reduced fertility",
     C_GREEN),
    ("SINUSES",
     "Chronic sinusitis (virtually all patients)\nNasal polyps (10-40%)",
     C_NAVY),
    ("BONE",
     "Osteoporosis/osteopenia | Short stature\nDelayed puberty | CF arthropathy",
     RGBColor(0x2E,0x86,0xAB)),
    ("CLUBBING &\nSKIN",
     "Digit clubbing (chronic hypoxia/bronchiectasis)\nWrinkling of hands/feet\nHypochloremic alkalosis",
     RGBColor(0x7B,0x68,0xEE)),
]):
    ci = i % 3; ri = i // 3
    xp = 0.3 + ci * 4.3; yp = 1.35 + ri * 1.82
    cbox(sl, name, xp, yp, 1.9, 0.65, col, size=10, bold=True)
    add_text(sl, desc, xp + 1.98, yp + 0.05, 2.25, 0.62, size=9, color=C_DARK)

dcs = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                          Inches(0.3), Inches(6.82), Inches(12.7), Inches(0.52))
dcs.fill.solid(); dcs.fill.fore_color.rgb = C_NAVY
dcs.line.fill.background(); dcs.shadow.inherit = False
add_text(sl, "Diagnostic Criteria (any ONE): ", 0.4, 6.87, 2.8, 0.38, size=12, bold=True, color=C_GOLD)
add_text(sl, "Sweat Cl- >=60 mEq/L (x2)  OR  Two pathogenic CFTR mutations  OR  Abnormal nasal potential difference"
             "  PLUS >=1 clinical feature / family history / positive newborn screen",
         3.25, 6.87, 9.8, 0.42, size=11, color=C_WHITE)

foot(sl, "Goldman-Cecil Medicine p.3231-3290 | Harrison's Principles of Internal Medicine 22E")

# ── REFERENCES ────────────────────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl, C_NAVY)
hdr(sl, "References", "Autosomal Recessive Inheritance", col=C_TEAL)
for i, r in enumerate([
    "1. Goldman L, Schafer AI. Goldman-Cecil Medicine. 27th ed. (International). Elsevier; 2024.",
    "2. Loscalzo J et al. Harrison's Principles of Internal Medicine. 22nd ed. McGraw-Hill; 2025.",
    "3. Thompson MW et al. Thompson & Thompson Genetics and Genomics in Medicine. 9th ed. Elsevier; 2023.",
    "4. Lieberman M, Peet A. Basic Medical Biochemistry: A Clinical Approach. 6th ed. Wolters Kluwer; 2024.",
    "5. GeneReviews: FBN1-Related Marfan Syndrome. NBK1335. NCBI Bookshelf.",
    "6. Stenson PD et al. The Human Gene Mutation Database (HGMD). Nucleic Acids Res. 2020;48(D1):D895-D900.",
    "7. Vockley J et al. Phenylalanine hydroxylase deficiency. Genet Med. 2014;16(2):188-200.",
]):
    add_text(sl, r, 0.5, 1.4 + i*0.72, 12.3, 0.65, size=12, color=C_WHITE)

buf = BytesIO(); prs.save(buf)
with open("/tmp/workspace/genetics-cbd/PPT3_Autosomal_Recessive.pptx", "wb") as f:
    f.write(buf.getvalue())
print("PPT3 saved OK")

Writing File

~/genetics-cbd/make_ppt4.py

"""PPT 4: Chromosomal Anomalies"""
from pptx import Presentation
from pptx.util import Inches, Pt
from pptx.dml.color import RGBColor
from pptx.enum.text import PP_ALIGN, MSO_ANCHOR
from pptx.enum.shapes import MSO_SHAPE, MSO_CONNECTOR
from io import BytesIO

C_NAVY   = RGBColor(0x0D,0x2B,0x6E)
C_TEAL   = RGBColor(0x00,0x7B,0x8A)
C_LIME   = RGBColor(0x6A,0xB1,0x87)
C_ORANGE = RGBColor(0xE8,0x8B,0x2E)
C_WHITE  = RGBColor(0xFF,0xFF,0xFF)
C_LIGHT  = RGBColor(0xF0,0xF6,0xFB)
C_DARK   = RGBColor(0x1A,0x1A,0x2E)
C_RED    = RGBColor(0xC0,0x39,0x2B)
C_GOLD   = RGBColor(0xF5,0xCB,0x5C)
C_PURPLE = RGBColor(0x7B,0x35,0x7B)
C_GREEN  = RGBColor(0x1A,0x7A,0x4A)

prs = Presentation()
prs.slide_width  = Inches(13.333)
prs.slide_height = Inches(7.5)
BLANK = prs.slide_layouts[6]

def bg(slide, color=C_LIGHT):
    s = slide.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, 0, prs.slide_width, prs.slide_height)
    s.fill.solid(); s.fill.fore_color.rgb = color
    s.line.fill.background(); s.shadow.inherit = False

def hdr(slide, title, subtitle="", col=C_NAVY):
    b = slide.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, 0, prs.slide_width, Inches(1.25))
    b.fill.solid(); b.fill.fore_color.rgb = col
    b.line.fill.background(); b.shadow.inherit = False
    t = slide.shapes.add_textbox(Inches(0.3), Inches(0.05), Inches(12), Inches(0.7))
    p = t.text_frame.paragraphs[0]; p.text = title
    r = p.runs[0]; r.font.size = Pt(28); r.font.bold = True
    r.font.color.rgb = C_WHITE; r.font.name = "Calibri"
    if subtitle:
        t2 = slide.shapes.add_textbox(Inches(0.35), Inches(0.78), Inches(12), Inches(0.45))
        p2 = t2.text_frame.paragraphs[0]; p2.text = subtitle
        r2 = p2.runs[0]; r2.font.size = Pt(14); r2.font.color.rgb = C_GOLD; r2.font.name = "Calibri"

def add_text(slide, text, x, y, w, h, size=13, bold=False, color=C_DARK,
             align=PP_ALIGN.LEFT, italic=False, wrap=True):
    box = slide.shapes.add_textbox(Inches(x), Inches(y), Inches(w), Inches(h))
    tf = box.text_frame; tf.word_wrap = wrap
    p = tf.paragraphs[0]; p.text = text; p.alignment = align
    r = p.runs[0]; r.font.size = Pt(size); r.font.bold = bold
    r.font.color.rgb = color; r.font.name = "Calibri"; r.font.italic = italic

def cbox(slide, text, x, y, w, h, bg_c, tc=C_WHITE, size=12, bold=False):
    s = slide.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                               Inches(x), Inches(y), Inches(w), Inches(h))
    s.fill.solid(); s.fill.fore_color.rgb = bg_c
    s.line.fill.background(); s.shadow.inherit = False
    tf = s.text_frame; tf.word_wrap = True; tf.vertical_anchor = MSO_ANCHOR.MIDDLE
    p = tf.paragraphs[0]; p.text = text; p.alignment = PP_ALIGN.CENTER
    r = p.runs[0]; r.font.size = Pt(size); r.font.color.rgb = tc
    r.font.bold = bold; r.font.name = "Calibri"

def foot(slide, ref):
    ln = slide.shapes.add_connector(MSO_CONNECTOR.STRAIGHT,
                                    Inches(0.3), Inches(7.15), Inches(13), Inches(7.15))
    ln.line.color.rgb = C_TEAL; ln.line.width = Pt(1)
    add_text(slide, ref, 0.3, 7.18, 12.7, 0.3, size=9, italic=True,
             color=RGBColor(0x55, 0x55, 0x55))

# ── TITLE ─────────────────────────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl, C_NAVY)
dec = sl.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, Inches(3.8), prs.slide_width, Inches(0.1))
dec.fill.solid(); dec.fill.fore_color.rgb = C_TEAL
dec.line.fill.background(); dec.shadow.inherit = False
dec2 = sl.shapes.add_shape(MSO_SHAPE.RECTANGLE, 0, Inches(3.9), prs.slide_width, Inches(0.04))
dec2.fill.solid(); dec2.fill.fore_color.rgb = C_GOLD
dec2.line.fill.background(); dec2.shadow.inherit = False
add_text(sl, "GENETICS CBD", 1, 1.2, 11, 0.6, size=22, color=C_GOLD, align=PP_ALIGN.CENTER)
add_text(sl, "CHROMOSOMAL ANOMALIES", 0.5, 2.0, 12.3, 1.1, size=46, bold=True, color=C_WHITE, align=PP_ALIGN.CENTER)
add_text(sl, "Definition  |  Down Syndrome  |  Jacob's Syndrome  |  Y-Linked Diseases  |  X-Linked Diseases",
         1, 3.25, 11.3, 0.6, size=15, color=C_GOLD, align=PP_ALIGN.CENTER)
add_text(sl, "Sources: Robbins & Kumar Basic Pathology | Thompson & Thompson Genetics 9th ed. | Emery's Elements of Medical Genetics",
         1, 6.8, 11.3, 0.5, size=10, italic=True,
         color=RGBColor(0xAA, 0xBB, 0xCC), align=PP_ALIGN.CENTER)

# ── SLIDE 16: DEFINITION ──────────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "16. Chromosomal Anomalies: Definition",
    "Abnormalities of chromosome number, structure, or both", col=C_NAVY)

add_text(sl, "A. Numerical Abnormalities (Aneuploidy)", 0.3, 1.35, 6.2, 0.38, size=14, bold=True, color=C_NAVY)
for i, (name, def_, ex, col) in enumerate([
    ("Monosomy (2n-1)", "Loss of 1 chromosome",           "45,X -- Turner syndrome",     C_RED),
    ("Trisomy (2n+1)",  "Extra chromosome",               "47,+21 -- Down syndrome",     C_ORANGE),
    ("Tetrasomy",       "Two extra of same type",         "48,XXXX",                     C_PURPLE),
    ("Polyploidy",      "Complete extra set (lethal)",    "Triploidy (69,XXX)",           RGBColor(0x5D,0x6D,0x7E)),
]):
    yp = 1.82 + i*0.68
    cbox(sl, name, 0.3, yp, 2.2, 0.55, col, size=11, bold=True)
    add_text(sl, def_, 2.6, yp + 0.06, 2.0, 0.45, size=11, color=C_DARK)
    add_text(sl, ex, 4.65, yp + 0.06, 1.65, 0.45, size=10, color=col, bold=True)

add_text(sl, "B. Structural Abnormalities", 0.3, 4.65, 6.2, 0.38, size=14, bold=True, color=C_TEAL)
for i, (name, def_, ex, col) in enumerate([
    ("Deletion",              "Loss of chromosomal segment",      "5p- (Cri-du-chat)",          C_RED),
    ("Duplication",           "Extra copy of segment",            "Dup 17p11.2 (CMT1A)",        C_ORANGE),
    ("Robertsonian transl.",  "Fusion of 2 acrocentric chrs",     "rob(14;21) in Down syndrome", C_TEAL),
    ("Reciprocal transl.",    "Exchange between non-homologs",    "t(9;22) -- Philadelphia chr", C_NAVY),
    ("Inversion",             "Reversed chromosomal segment",     "inv(9)",                     C_PURPLE),
]):
    yp = 5.1 + i*0.38
    cbox(sl, name, 0.3, yp, 2.2, 0.32, col, size=10, bold=True)
    add_text(sl, def_, 2.6, yp + 0.02, 2.0, 0.32, size=10, color=C_DARK)
    add_text(sl, ex, 4.65, yp + 0.02, 1.65, 0.32, size=9, color=col)

# Right panel
add_text(sl, "C. Special Categories", 6.8, 1.35, 6.2, 0.38, size=14, bold=True, color=C_NAVY)
for i, (name, mech, ex, col) in enumerate([
    ("Uniparental Disomy", "Both homologs from same parent",      "PWS/Angelman",    C_ORANGE),
    ("Mosaicism",          "Two or more different cell lines",    "Mosaic Down syn.", C_TEAL),
    ("Imprinting disorder","Epigenetic regulation disrupted",     "PWS/AS",          C_PURPLE),
]):
    yp = 1.82 + i*0.78
    cbox(sl, name, 6.8, yp, 2.2, 0.62, col, size=11, bold=True)
    add_text(sl, mech, 9.1, yp + 0.06, 2.5, 0.52, size=11, color=C_DARK)
    add_text(sl, ex, 11.65, yp + 0.06, 1.5, 0.52, size=10, color=col, bold=True)

add_text(sl, "Causes of Chromosomal Anomalies", 6.8, 4.22, 6.2, 0.38, size=14, bold=True, color=C_TEAL)
for i, c in enumerate([
    "Nondisjunction (most common): failure of chromosome separation in meiosis I or II",
    "Advanced maternal age: strongly associated with nondisjunction for most trisomies",
    "Chromosome breakage: radiation, chemical mutagens, repair errors",
    "Unequal recombination at segmental duplications (e.g., 15q11-q13)",
]):
    add_text(sl, "* " + c, 6.8, 4.65 + i*0.45, 6.2, 0.42, size=11, color=C_DARK)

freq = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                           Inches(6.8), Inches(6.55), Inches(6.2), Inches(0.62))
freq.fill.solid(); freq.fill.fore_color.rgb = C_NAVY
freq.line.fill.background(); freq.shadow.inherit = False
add_text(sl, "Frequency: ~1 in 160 live births | ~50% of spontaneous abortions are chromosomally abnormal",
         6.9, 6.6, 6.0, 0.52, size=11, color=C_WHITE)

foot(sl, "Thompson & Thompson Genetics 9th ed. | Emery's Elements of Medical Genetics | Robbins & Kumar Pathologic Basis of Disease")

# ── SLIDE 17: DOWN SYNDROME ───────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "17. Down Syndrome (Trisomy 21 / Mongolism)",
    "Most common chromosomal disorder | 1 in 700 live births", col=C_TEAL)

add_text(sl, "Karyotype Types", 0.3, 1.35, 5.5, 0.38, size=14, bold=True, color=C_NAVY)
for i, (ktype, pct, mech, col) in enumerate([
    ("47,XX or XY,+21\n(Free Trisomy)", "~95%",
     "Meiotic nondisjunction\n95% extra chr 21 is maternal origin", C_RED),
    ("46 with Robertsonian\ntranslocation rob(14;21)", "~4%",
     "Familial in some cases\nMaternal carrier: 45,XX,rob(14;21)", C_ORANGE),
    ("Mosaic (46/47\nmixed cell lines)", "~1%",
     "Mitotic nondisjunction in early embryo\nMilder phenotype possible", C_TEAL),
]):
    yp = 1.82 + i*1.0
    cbox(sl, ktype, 0.3, yp, 2.5, 0.72, col, size=11, bold=True)
    cbox(sl, pct,   2.88, yp + 0.1, 0.7, 0.52, col, size=14, bold=True)
    add_text(sl, mech, 3.65, yp + 0.1, 2.0, 0.52, size=10, color=C_DARK)

add_text(sl, "Maternal Age Risk", 0.3, 4.95, 5.5, 0.38, size=13, bold=True, color=C_TEAL)
for i, (age, risk, col) in enumerate([
    ("<20 yrs", "1:1,550", C_GREEN),
    ("30 yrs",  "1:900",   C_ORANGE),
    ("35 yrs",  "1:385",   C_ORANGE),
    ("40 yrs",  "1:100",   C_RED),
    (">=45 yrs","1:25",    C_RED),
]):
    cbox(sl, age,  0.3 + i*1.08, 5.38, 0.9, 0.42, C_NAVY, size=10, bold=True)
    cbox(sl, risk, 0.3 + i*1.08, 5.85, 0.9, 0.42, col,    size=10, bold=True)

# Clinical features grid
add_text(sl, "Clinical Features", 5.9, 1.35, 7.1, 0.38, size=14, bold=True, color=C_NAVY)
for i, (sys_name, desc, col) in enumerate([
    ("FACIAL",           "Flat face, epicanthal folds, upslanting palpebral fissures\nBrushfield spots, macroglossia, small ears", C_TEAL),
    ("CNS",              "Moderate-mild intellectual disability (IQ 40-70)\nHypotonia (universal at birth)", C_NAVY),
    ("CARDIAC\n(40%)",   "AVSD 43% | VSD 32% | ASD 19% | ToF 6%\nLeading cause of death in infancy", C_RED),
    ("GI",               "Duodenal atresia ('double bubble')\nHirschsprung disease", C_ORANGE),
    ("HAEMATOLOGY",      "20x ALL risk | 500x AML risk\nTransient myeloproliferative disorder (GATA1)", C_PURPLE),
    ("NEURODEGENERATION","Alzheimer in virtually ALL >40 yrs\n(APP gene x 3 -> excess amyloid-beta)", RGBColor(0x5D,0x6D,0x7E)),
    ("IMMUNOLOGY",       "Defective T-cell function -> infections\nThyroid autoimmunity 15-20%", RGBColor(0x2E,0x86,0xAB)),
    ("LIFE EXPECTANCY",  "Median 47 years (was 25 yrs in 1983)\nImproved with cardiac surgery", C_GREEN),
]):
    ci = i % 2; ri = i // 2
    xp = 5.9 + ci*3.55; yp = 1.82 + ri*1.22
    cbox(sl, sys_name, xp, yp, 1.8, 0.58, col, size=10, bold=True)
    add_text(sl, desc, xp + 1.88, yp + 0.04, 1.58, 0.55, size=9, color=C_DARK)

ps = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                         Inches(0.3), Inches(6.5), Inches(5.5), Inches(0.7))
ps.fill.solid(); ps.fill.fore_color.rgb = C_NAVY
ps.line.fill.background(); ps.shadow.inherit = False
add_text(sl, "Prenatal Screening:", 0.4, 6.55, 1.8, 0.3, size=12, bold=True, color=C_GOLD)
add_text(sl, "cfDNA/NIPT (>99% sensitivity) | 1st trim: NT + PAPP-A + b-hCG | 2nd trim: Quad screen | Confirm: amniocentesis/CVS + karyotype",
         0.4, 6.85, 5.3, 0.3, size=10, color=C_WHITE)

foot(sl, "Robbins & Kumar Pathologic Basis of Disease p.163-165 | Thompson & Thompson Genetics 9th ed. | Emery's Elements")

# ── SLIDE 18: JACOB'S SYNDROME ────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "18. Jacob's Syndrome (47,XYY)",
    "Sex chromosome aneuploidy | Extra Y chromosome | 1 in 1000 male births", col=C_ORANGE)

cbox(sl,
     "Karyotype: 47,XYY\nIncidence: 1 in 1,000 males\n"
     "Cause: Nondisjunction in PATERNAL meiosis II\n(Y chromatids fail to separate -- 100% paternal origin)",
     0.3, 1.35, 4.5, 1.35, C_NAVY, size=12, bold=True)

ms = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                         Inches(0.3), Inches(2.78), Inches(4.5), Inches(0.5))
ms.fill.solid(); ms.fill.fore_color.rgb = RGBColor(0xFE,0xF9,0xE7)
ms.line.color.rgb = C_ORANGE; ms.line.width = Pt(1.5); ms.shadow.inherit = False
add_text(sl, "Mosaicism (46,XY/47,XYY): post-zygotic mitotic error -- milder phenotype; ~10% of cases",
         0.4, 2.83, 4.3, 0.4, size=11, color=C_DARK)

add_text(sl, "Clinical Features", 0.3, 3.38, 4.5, 0.38, size=14, bold=True, color=C_NAVY)
for i, (dom, col, items) in enumerate([
    ("Physical", C_TEAL, [
        "Tall stature (>1.88m at final height)",
        "Macrocephaly | Hypertelorism",
        "Clinodactyly (5th finger) | Macrodontia",
        "Macroorchidism | Flat feet | Scoliosis",
    ]),
    ("Neurodevelopmental", C_ORANGE, [
        "Normal IQ range (slightly lower vs siblings)",
        "Language/reading delays (dyslexia)",
        "ADHD | Anxiety | Depression",
        "Autism spectrum disorder -- increased risk",
    ]),
    ("Medical", C_RED, [
        "Asthma (increased incidence)",
        "Seizures / tremors",
        "Genitourinary anomalies (some cases)",
        "Infertility: oligospermia in some",
    ]),
    ("Behavioral", C_PURPLE, [
        "Impulse control difficulties",
        "Emotional dysregulation",
        "NOT necessarily criminal/violent",
        "Many individuals fully normal",
    ]),
]):
    ci = i % 2; ri = i // 2
    xp = 0.3 + ci*2.25; yp = 3.82 + ri*1.62
    cbox(sl, dom, xp, yp, 2.0, 0.42, col, size=11, bold=True)
    for j, item in enumerate(items):
        add_text(sl, "* " + item, xp, yp + 0.48 + j*0.28, 2.1, 0.26, size=9, color=C_DARK)

add_text(sl, "Diagnosis & Management", 5.0, 1.35, 8.0, 0.38, size=14, bold=True, color=C_NAVY)
for i, (cat, desc) in enumerate([
    ("Prenatal",         "NIPT, amniocentesis, CVS -- karyotype 47,XYY confirmed"),
    ("Postnatal",        "Karyotype from blood lymphocytes | Median Dx age: ~17 yrs"),
    ("Speech therapy",   "Early language/speech intervention for language delays"),
    ("Educational",      "Individualized educational support for learning difficulties"),
    ("Behavioral",       "CBT, behavioral therapy for impulse control difficulties"),
    ("Occupational",     "Therapy for motor development delays"),
    ("Monitoring",       "Annual check for scoliosis | Endocrine evaluation if needed"),
    ("Genetic counseling","Most offspring have normal karyotype; ART available if infertile"),
]):
    cbox(sl, cat, 5.0, 1.82 + i*0.62, 1.8, 0.48, C_TEAL, size=10, bold=True)
    add_text(sl, desc, 6.9, 1.86 + i*0.62, 6.2, 0.46, size=10, color=C_DARK)

foot(sl, "NCBI Bookshelf NBK557699 | Cleveland Clinic | MedlinePlus Genetics | Emery's Elements of Medical Genetics")

# ── SLIDE 19: Y-LINKED DISEASES ───────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "19. Y-Linked (Holandric) Diseases",
    "Genes on Y chromosome -- father to ALL sons | NO daughters ever affected", col=C_GREEN)

cbox(sl,
     "Y-Linked Inheritance Rules:\n"
     "* Transmitted exclusively father to son (holandric)\n"
     "* ALL sons of affected father are affected\n"
     "* NO daughters affected -- ever\n"
     "* No female carriers possible",
     0.3, 1.35, 5.5, 1.22, C_NAVY, size=12, bold=True)

add_text(sl, "Y Chromosome Structure", 0.3, 2.68, 5.5, 0.38, size=13, bold=True, color=C_TEAL)
for x, lbl, col in [(0.3, "PAR1\n(Pseudoauto-\nsomal Region 1)\nPairs with X", C_TEAL),
                    (2.2, "MSY\nMale-Specific Y\n(Non-recombining)\nTruly Y-specific genes", C_NAVY),
                    (4.1, "PAR2\n(Pseudoauto-\nsomal Region 2)", C_TEAL)]:
    cbox(sl, lbl, x, 3.12, 1.8, 0.95, col, size=10, bold=True)
add_text(sl, "PAR1/2 pair with X during meiosis -- genes here are NOT exclusively Y-linked",
         0.3, 4.15, 5.5, 0.35, size=10, italic=True, color=C_DARK)

add_text(sl, "Key Y-Linked Genes & Diseases", 0.3, 4.62, 5.5, 0.38, size=13, bold=True, color=C_NAVY)
for i, (gene, loc, func, dis, col) in enumerate([
    ("SRY", "Yp11.3",
     "Sex determination -- initiates male sex development",
     "Mutations -> 46,XY sex reversal (female phenotype)", C_RED),
    ("AZFa/b/c loci\n(Azoospermia Factor)", "Yq11.2",
     "Spermatogenesis -- DAZ, RBMY, USP9Y",
     "Microdeletions -> azoospermia/oligospermia -> male infertility", C_ORANGE),
    ("Hypertrichosis\npinnae", "Y (debated)",
     "Hairy ear pinna -- classical holandric teaching example",
     "Father-to-all-sons transmission (now debated vs autosomal)", C_TEAL),
]):
    cbox(sl, gene, 0.3, 5.08 + i*0.58, 1.1, 0.48, col, size=10, bold=True)
    add_text(sl, "Loc: " + loc, 1.48, 5.1 + i*0.58, 0.9, 0.22, size=9, color=C_DARK)
    add_text(sl, func, 1.48, 5.3 + i*0.58, 2.2, 0.28, size=9, color=C_DARK)
    add_text(sl, dis, 3.75, 5.12 + i*0.58, 2.0, 0.42, size=9, color=col, bold=True)

# AZF deletions
add_text(sl, "Y Chromosome Microdeletions & Male Infertility", 6.0, 1.35, 7.0, 0.38, size=14, bold=True, color=C_NAVY)
for i, (del_name, desc, col) in enumerate([
    ("AZFa deletion",
     "Sertoli-cell-only syndrome -- NO germ cells present\nTESE: sperm retrieval UNLIKELY", C_RED),
    ("AZFb deletion",
     "Spermatogenic arrest -- sperm production halted\nTESE: sperm retrieval UNLIKELY", C_ORANGE),
    ("AZFc deletion",
     "Most common (50-60% of AZF deletions)\nVariable severity -- TESE often SUCCESSFUL", C_TEAL),
]):
    yp = 1.82 + i*1.0
    cbox(sl, del_name, 6.0, yp, 2.3, 0.55, col, size=11, bold=True)
    add_text(sl, desc, 8.4, yp + 0.05, 4.7, 0.5, size=11, color=C_DARK)

prev = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                           Inches(6.0), Inches(5.05), Inches(7.0), Inches(0.5))
prev.fill.solid(); prev.fill.fore_color.rgb = RGBColor(0xD5,0xF5,0xE3)
prev.line.color.rgb = C_GREEN; prev.line.width = Pt(1.5); prev.shadow.inherit = False
add_text(sl, "AZF deletion prevalence: ~7-10% of azoospermic men | ~5% of severely oligospermic men",
         6.1, 5.1, 6.8, 0.38, size=11, bold=True, color=C_DARK)

add_text(sl, "Klinefelter Syndrome (47,XXY) -- for comparison", 6.0, 5.65, 7.0, 0.38, size=13, bold=True, color=C_NAVY)
for i, k in enumerate([
    "Karyotype: 47,XXY (most common); XXYY, XXXY (increasingly severe)",
    "Incidence: 1 in 500-1,000 male births",
    "Features: tall | small testes | azoospermia | gynaecomastia | reduced testosterone | learning difficulties",
    "NOT holandric -- involves extra sex chromosome; often de novo nondisjunction",
]):
    add_text(sl, "* " + k, 6.0, 6.08 + i*0.29, 7.0, 0.27, size=10, color=C_DARK)

foot(sl, "Emery's Elements of Medical Genetics | Thompson & Thompson Genetics 9th ed. | NCBI/GeneReviews")

# ── SLIDE 20: X-LINKED DISEASES ───────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl)
hdr(sl, "20. X-Linked Diseases",
    "Hemizygous expression in males -- X-linked recessive and dominant patterns", col=C_RED)

lh = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                         Inches(0.3), Inches(1.35), Inches(12.7), Inches(0.52))
lh.fill.solid(); lh.fill.fore_color.rgb = RGBColor(0xFD,0xED,0xEC)
lh.line.color.rgb = C_RED; lh.line.width = Pt(2); lh.shadow.inherit = False
add_text(sl,
    "Lyon Hypothesis (X-Inactivation): One X chromosome randomly inactivated per somatic cell at ~16 days post-fertilization"
    " -- Barr body. Skewed X-inactivation (>90:10) can cause MANIFESTING CARRIERS of XLR diseases.",
    0.4, 1.4, 12.4, 0.42, size=11, color=C_DARK)

add_text(sl, "X-Linked RECESSIVE (XLR) Rules", 0.3, 1.97, 5.5, 0.38, size=13, bold=True, color=C_NAVY)
for i, r in enumerate([
    "Predominantly affects MALES (hemizygous -- only one allele)",
    "Females usually asymptomatic CARRIERS (heterozygous)",
    "Carrier mother: 50% sons affected | 50% daughters carriers",
    "Affected father: ALL daughters carriers | NO sons affected",
    "NO male-to-male transmission (KEY distinguishing feature from AD)",
    "Rare affected females: Turner syndrome / homozygous XLR / skewed X-inactivation",
]):
    cbox(sl, str(i+1), 0.3, 2.42 + i*0.44, 0.4, 0.37, C_RED, size=12, bold=True)
    add_text(sl, r, 0.82, 2.44 + i*0.44, 4.8, 0.36, size=10, color=C_DARK)

xld = sl.shapes.add_shape(MSO_SHAPE.ROUNDED_RECTANGLE,
                          Inches(0.3), Inches(5.12), Inches(5.5), Inches(1.55))
xld.fill.solid(); xld.fill.fore_color.rgb = RGBColor(0xD5,0xF5,0xE3)
xld.line.color.rgb = C_GREEN; xld.line.width = Pt(1.5); xld.shadow.inherit = False
add_text(sl, "X-Linked DOMINANT (XLD):", 0.4, 5.17, 3.0, 0.35, size=12, bold=True, color=C_GREEN)
for i, (name, desc) in enumerate([
    ("Rett Syndrome (MECP2)",          "Progressive neurological disorder; almost exclusively females (males lethal)"),
    ("Incontinentia Pigmenti (IKBKG)", "Skin/dental/CNS/eye; males die in utero"),
    ("Hypophosphatemic Rickets (PHEX)","Phosphate-wasting; affects both sexes; females less severe"),
]):
    add_text(sl, "* " + name + ":", 0.4, 5.56 + i*0.36, 2.1, 0.33, size=10, bold=True, color=C_GREEN)
    add_text(sl, desc, 2.5, 5.56 + i*0.36, 3.2, 0.33, size=10, color=C_DARK)

# Major XLR diseases table
add_text(sl, "Major X-Linked Recessive Diseases", 5.9, 1.97, 7.1, 0.38, size=13, bold=True, color=C_NAVY)
for i, (disease, gene, features, col) in enumerate([
    ("Duchenne MD",            "DMD (dystrophin) Xp21.2",
     "Progressive muscle wasting; Gowers' sign; wheelchair teens; dilated CM",      C_RED),
    ("Haemophilia A",          "F8 (Factor VIII) Xq28",
     "Severe bleeding; haemarthroses; absent/reduced FVIII",                         C_RED),
    ("Haemophilia B",          "F9 (Factor IX) Xq27.1",
     "Christmas disease; similar to Haemophilia A; reduced FIX",                     C_ORANGE),
    ("Fragile X Syndrome",     "FMR1 (CGG repeat) Xq27.3",
     "Most common inherited ID; macroorchidism; autism; large ears",                 C_PURPLE),
    ("Colour blindness",       "OPN1LW/MW Xq28",
     "Most common XL condition; ~8% males; red-green deficiency",                    C_TEAL),
    ("G6PD Deficiency",        "G6PD Xq28",
     "Haemolytic anaemia triggered by drugs/infections/fava beans",                  C_ORANGE),
    ("Fabry Disease",          "GLA (alpha-galactosidase A) Xq22",
     "Lysosomal storage; angiokeratomas; renal failure; cardiac disease",             C_NAVY),
    ("Lesch-Nyhan Syndrome",   "HPRT1 Xq26",
     "Gout + intellectual disability + self-mutilation; HGPRT deficiency",           C_RED),
    ("X-linked Agammaglob.",   "BTK (Bruton's TK) Xq21.33",
     "Absent B cells; recurrent bacterial infections (XLA)",                         C_GREEN),
    ("Wiskott-Aldrich",        "WAS Xp11.23",
     "Triad: eczema + thrombocytopenia + immunodeficiency",                          C_PURPLE),
]):
    ci = i % 2; ri = i // 2
    xp = 5.9 + ci*3.55; yp = 2.42 + ri*0.93
    cbox(sl, disease, xp, yp, 2.0, 0.5, col, size=10, bold=True)
    add_text(sl, gene, xp + 2.08, yp + 0.01, 1.35, 0.28, size=8, color=col, bold=True)
    add_text(sl, features, xp + 2.08, yp + 0.26, 1.38, 0.32, size=8, color=C_DARK)

foot(sl, "Emery's Elements of Medical Genetics | Thompson & Thompson Genetics 9th ed. | Robbins & Kumar Pathologic Basis of Disease")

# ── REFERENCES ────────────────────────────────────────────────────────────────
sl = prs.slides.add_slide(BLANK); bg(sl, C_NAVY)
hdr(sl, "References", "Chromosomal Anomalies", col=C_TEAL)
for i, r in enumerate([
    "1. Robbins R, Kumar V. Robbins & Kumar Basic Pathology. 11th ed. Elsevier; 2023. p.163-165.",
    "2. Thompson MW et al. Thompson & Thompson Genetics and Genomics in Medicine. 9th ed. Elsevier; 2023.",
    "3. Turnpenny P, Ellard S. Emery's Elements of Medical Genetics and Genomics. 16th ed. Elsevier; 2022.",
    "4. Bull MJ. Down syndrome. N Engl J Med. 2020;382:2344-2352.",
    "5. Tartaglia NR et al. 47,XYY syndrome. StatPearls/NCBI Bookshelf NBK557699. 2023.",
    "6. Cleveland Clinic. 47,XYY Syndrome (Jacobs Syndrome). my.clevelandclinic.org. 2024.",
    "7. Vogt PH et al. Human Y chromosome azoospermia factors (AZF). Hum Reprod. 1996;11:1459-1466.",
    "8. Goldman L, Schafer AI. Goldman-Cecil Medicine. 27th ed. International ed. Elsevier; 2024.",
]):
    add_text(sl, r, 0.5, 1.4 + i*0.65, 12.3, 0.58, size=12, color=C_WHITE)

buf = BytesIO(); prs.save(buf)
with open("/tmp/workspace/genetics-cbd/PPT4_Chromosomal_Anomalies.pptx", "wb") as f:
    f.write(buf.getvalue())
print("PPT4 saved OK")

Your credits are exhausted. You can purchase a top-up or subscribe to a plan to continue using Orris. If you're already subscribed, your daily credits will reset tomorrow.

This is a shared conversation. Sign in to Orris to start your own chat.