---

Genetic Disorders — Complete MBBS Guide

---

1. CLASSIFICATION OF GENETIC DISORDERS

"Monogenic disorders are generally rare unless maintained by selective forces, e.g., sickle cell in malaria-endemic areas." — Robbins, Cotran & Kumar Pathologic Basis of Disease

---

2. MUTATIONS — TYPES AND MECHANISMS

Types of mutations:

---

3. INHERITANCE PATTERNS

3.1 Autosomal Dominant (AD)

• One mutant allele sufficient to cause disease
• Every generation affected; 50% of offspring of an affected parent are affected
• Skipping of generations is due to incomplete penetrance or variable expressivity
• Gain-of-function mutations (dominant negative effect) are common
• Examples: Marfan syndrome, Familial hypercholesterolemia (heterozygous), Huntington's disease, Neurofibromatosis type 1 & 2, Achondroplasia, BRCA-related cancers (haploinsufficiency)

3.2 Autosomal Recessive (AR)

• Both alleles must be mutant to cause disease
• Carrier parents (heterozygotes) are phenotypically normal
• 25% of offspring affected; 50% carriers; 25% normal
• Loss-of-function enzyme defects are typically AR
• Examples: Cystic fibrosis, Sickle cell disease, PKU, Tay-Sachs, Niemann-Pick, Gaucher disease, Hurler syndrome

3.3 X-Linked Recessive (XR)

• Males (hemizygous) are almost always affected; females are carriers
• No male-to-male transmission
• Examples: Duchenne/Becker MD, Hemophilia A & B, G6PD deficiency, Hunter syndrome (MPS II), Fragile X (partially)

3.4 X-Linked Dominant (XD)

• Heterozygous females and hemizygous males are affected
• Some are lethal in males (e.g., Incontinentia pigmenti, Rett syndrome)
• Example: X-linked hypophosphatemia (vitamin D-resistant rickets)

3.5 Y-Linked (Holandric)

• Only males; all sons of affected father are affected
• Rare examples: genes on non-pseudoautosomal regions

---

4. BIOCHEMICAL BASIS OF MENDELIAN DISORDERS

---

5. KEY SINGLE-GENE (MENDELIAN) DISORDERS

5.1 Marfan Syndrome (AD)

• Gene: FBN1 (fibrillin-1) on chromosome 15q21 → missense mutations
• Fibrillin-1 is a glycoprotein essential for formation of elastic microfibrils (connective tissue scaffold)
• Loss of fibrillin also dysregulates TGF-β signaling (excess TGF-β activity drives many manifestations)

• Tall stature, long limbs (dolichostenomelia), arachnodactyly, high-arched palate
• Pectus excavatum, scoliosis, joint hypermobility
• Ectopia lentis (upward lens dislocation) — bilateral, pathognomonic
• Cardiovascular (most dangerous): Mitral valve prolapse, cystic medial necrosis of aorta → aortic root dilation, aortic regurgitation, aortic dissection (most common cause of death)
• Thumb sign (Steinberg) and wrist sign (Walker-Murdoch) are clinical clues

5.2 Familial Hypercholesterolemia (AD)

• Gene: LDLR (LDL receptor) on chromosome 19p13 — >2000 mutations known
• Pathogenesis: Defective LDL receptor → impaired uptake of LDL → elevated plasma LDL → atherosclerosis + xanthomas
• Heterozygotes: LDL 2–3× normal → premature atherosclerosis, xanthelasma, tendon xanthomas
• Homozygotes: LDL 5–6× normal → MI in childhood
• Six classes of LDL receptor mutations:
  • Class I: No synthesis (null allele)
  • Class II: Transport defect (ER accumulation)
  • Class III: Ligand-binding defect
  • Class IV: Internalization defect (coated pit failure)
  • Class V: Recycling defect (receptor trapped in endosome)
  • Class VI: Targeting defect (misdirected to apical surface)
• Treatment: Statins (↑LDL receptor synthesis by inhibiting HMG-CoA reductase) + PCSK9 inhibitors (↑LDL receptor by preventing its degradation)

5.3 Cystic Fibrosis (AR)

• Gene: CFTR on chromosome 7q31 — most common mutation is ΔF508 (deletion of phenylalanine at position 508)
• Protein: CFTR = cAMP-regulated Cl⁻/HCO₃⁻ channel in epithelial cells
• Class II mutation (ΔF508) → misfolded CFTR protein → retained in ER → degraded by proteasome
• Pathophysiology: Defective anion transport → thick, dehydrated secretions
  • Lungs: Viscid mucus → chronic Pseudomonas/Staphylococcus infections → bronchiectasis, emphysema
  • Pancreas: Ductal obstruction → exocrine pancreatic insufficiency, malabsorption, diabetes
  • Sweat glands: Elevated sweat Cl⁻ (>60 mEq/L) — diagnostic
  • Testes: Bilateral absence of vas deferens → infertility in males
• Diagnosis: Sweat chloride test; CFTR mutation analysis
• New therapy: CFTR modulators (ivacaftor/lumacaftor — for specific mutations)

5.4 Phenylketonuria (AR)

• Gene: PAH (phenylalanine hydroxylase) on chromosome 12q24
• Inability to convert phenylalanine → tyrosine → accumulation of phenylalanine + phenylketones
• Features: Intellectual disability, fair skin, musty odor, eczema, seizures
• Detected by Guthrie test (neonatal heel-prick screening)
• Treatment: Phenylalanine-restricted diet from birth; sapropterin (BH4 cofactor) for some variants

5.5 Lysosomal Storage Diseases

Gaucher disease is the most common lysosomal storage disease. It has a strong association with Parkinson disease. Type I is compatible with a long life; enzyme replacement therapy (imiglucerase) is available.

5.6 Glycogen Storage Diseases (GSD)

---

6. CHROMOSOMAL DISORDERS

6.1 Key Terminology

• Karyotype: Display of metaphase chromosomes (22 autosomes + XX/XY)
• Euploid: Normal multiple of haploid number (23)
• Aneuploid: Abnormal number (not a multiple of 23)
• Trisomy: 47 chromosomes (extra chromosome)
• Monosomy: 45 chromosomes (missing one)
• Nondisjunction: Failure of chromosome separation during meiosis I or II → aneuploidy
• Translocation: Segment of one chromosome attaches to another
  • Robertsonian: Long arms of two acrocentric chromosomes fuse (seen in ~4% of Down syndrome)
• Deletion: Loss of chromosomal segment
• Inversion: Segment reverses orientation

6.2 Autosomal Chromosomal Disorders

Trisomy 21 — Down Syndrome (most common chromosomal disorder compatible with life)

Trisomy 18 — Edwards Syndrome

• Incidence: 1 in 8000; severe intellectual disability; 90% die within 1 year
• Features: Clenched fists with overlapping fingers, rocker-bottom feet, micrognathia, CHD (VSD, PDA), renal malformations, horseshoe kidney
• Prominent occiput

Trisomy 13 — Patau Syndrome

• Incidence: 1 in 15,000; most severe; >80% die within 1 month
• Features: Holoprosencephaly, cyclopia, cleft lip/palate, polydactyly, CHD, microphthalmia, punched-out scalp lesions

22q11.2 Deletion Syndrome (DiGeorge / Velocardiofacial)

• Deletion of chromosome 22q11.2 — most common microdeletion syndrome
• CATCH-22 mnemonic: Cardiac defects (conotruncal), Abnormal facies, Thymic hypoplasia (T-cell deficiency → infections), Cleft palate, Hypocalcemia (parathyroid aplasia)
• Also: schizophrenia risk (1/3 develop psychiatric disorder), learning disabilities

6.3 Sex Chromosome Disorders

Klinefelter Syndrome (47,XXY)

Turner Syndrome (45,X)

47,XYY Syndrome

• Males; tall stature; mildly ↓ IQ; behavioral issues; fertile (usually)
• Not associated with increased criminal behavior (old misconception)

47,XXX Syndrome (Triple X)

• Females; usually phenotypically normal; mild learning difficulties; fertile

---

7. SINGLE-GENE DISORDERS WITH NON-CLASSIC INHERITANCE

7.1 Trinucleotide Repeat Expansion Disorders

Fragile X Syndrome (most common inherited cause of intellectual disability)

• Inheritance: X-linked but shows anticipation and maternal transmission bias
• Premutation (55–200 CGG): Mothers are asymptomatic carriers; in male offspring premutation can expand to full mutation
• Full mutation (>200 CGG): Hypermethylation → silencing of FMR1 → loss of FMRP (fragile X mental retardation protein, an RNA-binding protein essential for synaptic development)
• Features in males: Intellectual disability (IQ 20–60), macro-orchidism (large testes), long face with large jaw, large ears, autism-like behaviors
• FXTAS (Fragile X-associated Tremor/Ataxia Syndrome): Premutation carriers (especially males >50 yrs) → cerebellar ataxia, tremor, cognitive decline — gain-of-function RNA toxicity
• FXPOI (Primary Ovarian Insufficiency): Female premutation carriers → early menopause

7.2 Mitochondrial Inheritance

• Mitochondrial DNA (mtDNA) is maternally inherited (all mitochondria come from the egg)
• All children of an affected mother are affected (to variable degrees); no male-to-male transmission
• Heteroplasmy: Cells contain both wild-type and mutant mtDNA → variable expression
• Threshold effect: Disease manifests when mutant mtDNA exceeds a critical proportion in a tissue
• Most affected tissues are highly energy-dependent: brain, skeletal/cardiac muscle, liver, kidneys

• Mitochondrial gene mutation (most commonly in complex I subunit genes: ND1, ND4, ND6)
• Progressive bilateral loss of central vision, onset ages 15–35
• Also cardiac conduction defects, mild neurological features in some families

7.3 Genomic Imprinting

• Maternal imprinting = maternal allele silenced → only paternal allele expressed
• Paternal imprinting = paternal allele silenced → only maternal allele expressed

Uniparental Disomy (UPD): Both chromosomes of a pair inherited from the same parent → if imprinted genes are involved, this phenocopies deletion syndromes.

7.4 Gonadal Mosaicism

• A germline mutation arises post-fertilization but before germ cell determination → mutation is present in some germ cells but not somatic cells
• Significance: Phenotypically normal parents can have multiple affected children (mimics dominant inheritance skipping generations)
• Important in: osteogenesis imperfecta, Duchenne MD, achondroplasia

7.5 Somatic Mosaicism

• Mutation arises in somatic cells early in development → proportion of affected cells varies
• Results in patchy/asymmetric manifestations
• Example: McCune-Albright syndrome (GNAS activating mutation → fibrous dysplasia, precocious puberty, café-au-lait spots)

---

8. COMPLEX MULTIGENIC (MULTIFACTORIAL) DISORDERS

• Result from additive effects of multiple susceptibility alleles (each of low penetrance individually) interacting with environmental triggers
• Quantitative traits (height, blood pressure, blood glucose) follow a Gaussian distribution in populations
• Common examples: Type 2 diabetes, hypertension, coronary artery disease, schizophrenia, neural tube defects, cleft lip/palate, pyloric stenosis
• Recurrence risk ∝ severity of disease, number of affected relatives, closeness of relationship
• Carter effect: Males have higher threshold for pyloric stenosis; female probands → higher recurrence risk in relatives (relatives of a lower-risk sex who is affected harbor more susceptibility genes)

---

9. MOLECULAR DIAGNOSIS OF GENETIC DISORDERS

9.1 Indications for Genetic Testing

• Advanced maternal age (>34 yrs) → ↑ trisomy risk
• Balanced translocation carrier parent
• Fetal abnormalities on ultrasound / abnormal maternal serum screen
• Previous child with chromosomal/Mendelian disorder
• Carrier of X-linked disorder (to determine fetal sex)

• Multiple congenital anomalies
• Unexplained intellectual disability/developmental delay
• Suspected aneuploidy (Down, Turner, Klinefelter)
• Infertility
• Recurrent spontaneous abortions

9.2 Key Diagnostic Techniques

---

10. QUICK COMPARISON TABLE — HIGH-YIELD MBBS FACTS

---

11. PRENATAL SCREENING SUMMARY

---

12. MNEMONICS FOR QUICK RECALL

• Lysosomal storage diseases → AR (except Hunter = XR)
• CATCH-22 = DiGeorge features (Cardiac, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia — chromosome 22)
• Trinucleotide repeats → "GAC" disorders: Grappling with anticipation → CGG (Fragile X), CAG (Huntington, SCA), CTG (Myotonic dystrophy), GAA (Friedreich ataxia)
• Prader-Willi = Paternal deletion (both P's); Angelman = mAternal deletion (A = mAternal)
• Turner syndrome → "Monosomy X" = one X = one shape like "T" upside down → Short stature, Streak ovaries
• Klinefelter = extra X in male → feminizing features (gynecomastia, wide hips) + infertility

---

---

1. Classification — The 4 categories: Monogenic, Chromosomal, Multifactorial, Somatic
2. Mutation types — Point, frameshift, splice site, trinucleotide repeats, CNVs
3. Inheritance patterns — AD, AR, XR, XD, Y-linked with rules and examples
4. Biochemical basis — Structural protein defects, enzyme defects, receptor/transport defects
5. Key Mendelian disorders — Marfan, familial hypercholesterolemia (LDL receptor classes I–VI), cystic fibrosis (CFTR/ΔF508), PKU, all lysosomal storage diseases, glycogen storage diseases
6. Chromosomal disorders — Trisomy 21, 18, 13; 22q11.2 deletion (DiGeorge/CATCH-22); Klinefelter; Turner; 47,XYY; 47,XXX
7. Non-classic inheritance — Trinucleotide repeats (Fragile X, Huntington, myotonic dystrophy, Friedreich); Mitochondrial inheritance (LHON, heteroplasmy, threshold effect); Genomic imprinting (Prader-Willi vs. Angelman); Mosaicism
8. Multifactorial disorders — Carter effect, recurrence risk principles
9. Molecular diagnostics — Karyotype, FISH, PCR, array CGH, NGS, cfDNA/NIPT
10. High-yield tables and mnemonics for quick exam revision