---

GENETICS IN ANATOMY - EMBRYOLOGY

Exam-Oriented Notes

---

1. BASIC CHROMOSOME TERMINOLOGY

---

2. MEIOSIS - KEY CONCEPTS

Normal Meiotic Division

Primary Oocyte (46 chromosomes)
        ↓  Meiosis I (reductive division)
Secondary Oocyte (23 chromosomes) + 1st Polar Body
        ↓  Meiosis II
Mature Ovum (23 chromosomes) + 2nd Polar Body

Primary Spermatocyte (46 chromosomes)
        ↓  Meiosis I
2 Secondary Spermatocytes (23 each)
        ↓  Meiosis II
4 Spermatids → 4 Mature Spermatozoa

Key point (exam): In oogenesis, ONE oocyte + THREE polar bodies (degenerate); in spermatogenesis, ALL FOUR become functional spermatozoa.

---

3. NONDISJUNCTION - THE ROOT CAUSE OF ANEUPLOIDY

NORMAL MEIOSIS I:        NONDISJUNCTION (Meiosis I):
Homologs separate        Both homologs → SAME cell

Cell A: 23 chromosomes   Cell A: 24 chromosomes (n+1)
Cell B: 23 chromosomes   Cell B: 22 chromosomes (n-1)

After fertilization with normal 23:
→ 46 (normal)            → 47 (TRISOMY) or 45 (MONOSOMY)

• Nondisjunction can occur in Meiosis I or Meiosis II
• Incidence of chromosomal abnormalities increases with maternal age, especially after age 35
• 75% of Down syndrome nondisjunction occurs during oocyte formation (maternal)

---

4. CHROMOSOMAL ABNORMALITIES - OVERVIEW

• 50% of all conceptions end in spontaneous abortion
• 50% of abortuses have major chromosomal abnormalities
• Therefore ~25% of all conceptuses have a major chromosomal defect
• Chromosomal abnormalities account for 10% of major birth defects
• Gene mutations account for an additional 8% of birth defects

1. 45,X (Turner syndrome)
2. Triploidy
3. Trisomy 16

---

5. TYPES OF CHROMOSOMAL ABNORMALITIES

A. Numerical Abnormalities

B. Structural Abnormalities

Common translocations: Particularly common between chromosomes 13, 14, 15, 21, and 22 because they cluster during meiosis (acrocentric chromosomes - Robertsonian translocation).

---

6. AUTOSOMAL TRISOMIES - HIGH YIELD TABLE

Down Syndrome - Causes (Exam Breakdown)

Exam trap: Translocation Down syndrome shows NO maternal age effect and is the familial form. The carrier parent has a balanced translocation (45 chromosomes, phenotypically normal).

---

7. SEX CHROMOSOME ABNORMALITIES

Key Concept: X-Inactivation (Lyon Hypothesis)

• In females (XX), one X chromosome is randomly inactivated in each somatic cell early in development
• The inactive X condenses into a Barr body (sex chromatin)
• Number of Barr bodies = Number of X chromosomes - 1

---

Sex Chromosome Disorder Comparison Table

---

8. MODES OF MENDELIAN INHERITANCE

A. Autosomal Dominant (AD)

Affected parent (Aa) × Normal (aa)
Offspring: 50% Aa (affected) : 50% aa (normal)

• Both sexes affected equally
• Vertical transmission (every generation)
• Father-to-son transmission possible
• New mutations: unaffected parents can have affected child (sporadic)

• Reduced penetrance: Person carries mutation but shows no symptoms
• Variable expressivity: Same gene, different severity (e.g., neurofibromatosis)
• Late onset possible (e.g., Huntington disease)
• Usually involves structural proteins, NOT enzymes (because 50% enzyme activity can be compensated)

---

B. Autosomal Recessive (AR)

Carrier father (Aa) × Carrier mother (Aa)
Offspring: 25% AA : 50% Aa (carrier) : 25% aa (affected)

• Both sexes affected equally
• Horizontal transmission (one generation; siblings)
• Parents usually unaffected (carriers)
• Consanguinity increases risk
• Usually involves enzyme deficiencies

---

C. X-Linked Recessive (XLR)

Carrier mother (X^A X^a) × Normal father (X^A Y)
Sons: 50% affected (X^a Y) : 50% normal (X^A Y)
Daughters: 50% carrier (X^A X^a) : 50% normal (X^A X^A)

• Males predominantly affected
• No father-to-son transmission
• All daughters of affected males are obligate carriers
• Carrier females may show mild features (lyonization)

---

D. X-Linked Dominant (XLD)

• Both males and females affected
• Affected male → ALL daughters affected, NO sons affected
• Rarer - examples: Vitamin D-resistant rickets (hypophosphatemia), Rett syndrome

---

E. Y-Linked (Holandric)

• Only males; passed from father to ALL sons
• Examples: azoospermia factor (AZF), some genes on the Y chromosome

---

9. INHERITANCE PATTERN COMPARISON - QUICK REFERENCE

              AD    AR    XLR   XLD
Males = Females?   YES   YES   NO    MOSTLY
Skips generations? NO    YES   YES   NO
Father→Son?        YES   YES   NO    NO
Consanguinity?     NO    YES   NO    NO
Enzyme defect?     RARE  YES   YES   RARE
New mutations?     YES   RARE  YES   RARE

---

10. SPECIAL / ATYPICAL PATTERNS OF INHERITANCE

A. Mitochondrial Inheritance

• Mitochondrial DNA (mtDNA) is maternally inherited (sperm contributes no mitochondria)
• Affects both sexes but NEVER transmitted by fathers
• Variable expressivity due to heteroplasmy (mixture of normal and mutant mitochondria)
• Examples: MELAS, MERRF, Leber hereditary optic neuropathy (LHON)

B. Genomic Imprinting

• Some genes are expressed only from one parental allele (maternal or paternal), regardless of mutations

Memory trick: Prader-Willi = Paternal deletion; Angelman = mAternAl deletion

C. Triplet Repeat Mutations (Trinucleotide Repeats)

• Most common inherited cause of intellectual disability
• FMR1 gene - expansion of CGG repeat on X chromosome
• Premutation (55-200 CGG): carriers; females at risk for premature ovarian failure; males at risk for Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)
• Full mutation (>200 CGG): FXS - intellectual disability, large ears, macroorchidism (post-pubertal), long face

---

11. CYTOGENETIC DIAGNOSTIC TECHNIQUES

---

12. 22q11.2 DELETION SYNDROME (DiGeorge / VCFS / Catch-22)

• Caused by deletion of chromosome 22q11.2
• Detectable by FISH (loss of one FISH signal for the 22q11 region)
• Features (CATCH-22 mnemonic):
  • C - Cardiac defects (conotruncal defects: truncus arteriosus, tetralogy of Fallot)
  • A - Abnormal facies
  • T - Thymic aplasia (T-cell immunodeficiency)
  • C - Cleft palate
  • H - Hypocalcemia (absent parathyroid glands)
  • 22 - Chromosome 22

---

13. BIRTH DEFECTS - CAUSES SUMMARY

---

14. EXAM RAPID-FIRE TABLE: KEY ASSOCIATIONS

---

15. CLINICAL CORRELATES - HOW TO SPOT PATTERNS IN MCQs

• Every generation affected, father-to-son: → Autosomal Dominant
• Only siblings affected, parents normal, consanguineous: → Autosomal Recessive
• Males affected, maternal uncles affected, no father-to-son: → X-Linked Recessive
• Older mother, child with intellectual disability + flat facies: → Down syndrome (Trisomy 21)
• Young mother, child with same features: → Think Translocation Down syndrome (no maternal age effect)
• Short female, primary amenorrhea, webbed neck: → Turner syndrome (45,X)
• Tall male, small testes, gynecomastia: → Klinefelter syndrome (47,XXY)
• Intellectual disability + large ears + macroorchidism in male: → Fragile X syndrome
• Infant with hypocalcemia + conotruncal heart defect + immunodeficiency: → DiGeorge / 22q11.2 deletion
• Obese child, hypotonic, small hands/feet: → Prader-Willi
• "Happy puppet" child, severe ID, seizures: → Angelman

---

• Langman's Medical Embryology (Birth Defects and Chromosomal Factors chapter, pp. 37-44)
• Robbins & Kumar Basic Pathology (Genetic and Pediatric Diseases chapter, pp. 103-107)