---

Genetics: Key Topics

---

1. Autosomal Dominant Inheritance

Definition

Key Characteristics

Pedigree Features

• Affected individuals in multiple generations (vertical transmission)
• No skipping of generations (unlike recessive)
• Both sexes affected equally
• Male-to-male transmission is possible (distinguishes it from X-linked dominant)

Mechanisms of Dominant Expression

1. Haploinsufficiency — one functional copy is insufficient (e.g., PAX genes)
2. Dominant negative effect — mutant protein interferes with normal protein (e.g., collagen disorders)
3. Gain of function — mutant allele acquires a new, abnormal activity (e.g., Huntington disease)

Penetrance & Expressivity

• Penetrance: Proportion of individuals with the genotype who show the phenotype. Many AD conditions show incomplete penetrance (e.g., BRCA1/2 — 50–70% lifetime cancer risk, not 100%) (Harrison's, p. 13277)
• Expressivity: Degree to which the phenotype is expressed (variable expressivity common)

Important Examples

---

2. Gene Therapy

Definition

Types by Strategy

Vectors Used

Delivery Routes

• Ex vivo: Cells removed from patient → transfected in lab → reinfused (e.g., hematopoietic stem cells for SCID)
• In vivo: Vector delivered directly into the patient's body (e.g., intravitreal injection for retinal disease)
• In situ: Delivered locally at the disease site

Target Cells

Clinical Applications

Challenges

• Immune response to vectors
• Risk of insertional mutagenesis (retroviral vectors)
• Limited payload capacity (AAV: ~4.7 kb)
• Off-target effects with CRISPR
• High cost and manufacturing complexity
• Ethical concerns (germline editing)

---

3. Sex Chromatin

Definition

Lyon Hypothesis (X-Inactivation)

1. One X chromosome is inactivated in every somatic cell of females
2. Inactivation is random — either the maternal or paternal X may be inactivated in any given cell
3. Inactivation occurs early in embryonic development (~day 16)
4. Inactivation is permanent and clonal — all daughter cells maintain the same inactive X
5. The inactive X is called the Barr body (sex chromatin)
6. The inactive X is not entirely silenced — ~15–25% of genes escape inactivation (important for Turner syndrome features)

Number of Barr Bodies

Barr bodies = Number of X chromosomes − 1

Detection

• Buccal smear (cheek cells) stained with cresyl violet or Feulgen stain
• Barr body appears as a plano-convex dense mass at the inner surface of the nuclear membrane
• Present in ~20–60% of female cells in a normal buccal smear

Y Chromatin (F-body)

• Fluorescent spot seen in male cells when stained with quinacrine
• One Y chromosome = one F-body
• Seen in ~30–60% of male cells
• Formula: F-bodies = number of Y chromosomes

Clinical Significance

• Used in sex determination (especially in intersex conditions)
• Klinefelter syndrome (47,XXY): 1 Barr body — appears male phenotypically
• Turner syndrome (45,X): 0 Barr bodies — appears female phenotypically
• Triple X (47,XXX): 2 Barr bodies — usually normal phenotype

---

4. Structural Anomalies of Chromosomes

Definition

Types

A. Deletions

• Terminal deletion: Loss of segment from the end
• Interstitial deletion: Loss of internal segment (two breaks required)

B. Duplications

• Generally less harmful than deletions
• Example: Charcot-Marie-Tooth disease type 1A — duplication of 17p11.2

C. Inversions

• Paracentric inversion: Does not include the centromere (within one arm)
• Pericentric inversion: Includes the centromere (spans both arms)
• Usually balanced — no gain or loss of material; carrier often phenotypically normal
• Risk: recombinant chromosomes with deletions/duplications in offspring
• Example: Inv(9) — common polymorphism, usually benign

D. Translocations

• Carrier: 45 chromosomes (but balanced — normal phenotype)
• Offspring risk: ~10–15% risk of Down syndrome (translocation trisomy 21)
• Recurrence risk is higher than sporadic trisomy 21

E. Isochromosomes

• Example: i(Xq) — most common structural abnormality in Turner syndrome

F. Ring Chromosomes

• Loss of telomeric material → variable phenotype
• Example: Ring chromosome 13, ring chromosome X

G. Marker Chromosomes

Mechanisms of Formation

• Non-allelic homologous recombination (NAHR): most common for recurrent deletions/duplications
• Non-homologous end joining (NHEJ)
• Fork stalling and template switching (FoSTeS)

---

5. Trisomy 21 (Down Syndrome)

Definition

Incidence

• ~1 in 700–800 live births (most common chromosomal aneuploidy)
• Incidence increases sharply with maternal age (age >35 = significantly increased risk)
• Most common cause of intellectual disability due to a chromosomal anomaly

Cytogenetic Types

Clinical Features

• Flat facial profile, flat nasal bridge
• Upward slanting palpebral fissures (mongoloid slant)
• Epicanthal folds
• Brushfield spots (speckled iris)
• Protruding tongue, small ears, open mouth
• Brachycephaly, flat occiput

• Hypotonia (marked at birth)
• Hyperflexibility of joints
• Single palmar crease (Simian crease) — 50%
• Wide gap between 1st and 2nd toes ("sandal gap")
• Short stature, short neck with excess skin

• Intellectual disability (mild-to-moderate; IQ typically 35–70)
• Early-onset Alzheimer disease (virtually all develop AD neuropathology by age 40; gene for amyloid precursor protein — APP — is on chromosome 21)
• Hypotonia leading to motor delay

• Congenital heart disease in 40–50%
• Most common: AVSD (atrioventricular septal defect / endocardial cushion defect)
• VSD, ASD, PDA also common

• Duodenal atresia ("double bubble" sign on X-ray)
• Hirschsprung disease
• Annular pancreas
• Increased risk of celiac disease

• Increased risk of leukemia — especially AML (particularly AML-M7, megakaryoblastic) and ALL
• Transient myeloproliferative disorder (TMD) in neonates
• Polycythemia

• Hypothyroidism (Hashimoto's thyroiditis — increased autoimmune disease risk)
• Diabetes mellitus

• Increased susceptibility to infections
• Increased autoimmune disease

• Atlanto-axial instability
• Obstructive sleep apnea
• Infertility in males (azoospermia); females can be fertile

Diagnosis

• First trimester: Nuchal translucency (NT) + free β-hCG + PAPP-A (combined test)
• Second trimester Quadruple screen: AFP↓, hCG↑, uE3↓, Inhibin A↑
• NIPT (cell-free fetal DNA): High sensitivity (~99%) and specificity — detects fetal chromosomal DNA in maternal blood
• Definitive diagnosis: Amniocentesis or chorionic villus sampling (CVS) → karyotype

• Clinical features + karyotyping
• FISH for rapid confirmation

Management

• No curative treatment; multidisciplinary care
• Cardiac evaluation (echocardiography) in all neonates
• Thyroid function tests annually
• Hearing and vision screening
• Early intervention: physiotherapy, speech therapy, special education
• Regular cervical spine X-rays for atlanto-axial instability (especially before surgery/sports)
• Genetic counseling for parents

Key Associations to Remember

• Chromosome 21 genes: APP (Alzheimer), ERG (leukemia), DYRK1A (brain), RCAN1 (cardiac)
• Maternal age effect: Risk at age 20 = 1/1500; age 35 = 1/350; age 45 = 1/25
• Robertsonian translocation carrier mother (t(14;21)): ~10–15% risk; carrier father: ~2–3% risk
• t(21;21) carrier: 100% of viable offspring will have Down syndrome

---

Sources: Harrison's Principles of Internal Medicine, 21st Edition (pp. 2873, 13277); Thompson & Thompson Genetics in Medicine; Robbins & Cotran Pathologic Basis of Disease.