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AN75.1-5 | Principles of Genetics, Chromosomal Aberrations & Clinical Genetics — Self-Directed Learning
CLINICAL SCENARIO
A 38-year-old primigravida is referred to MGMCRI foetal medicine unit after a nuchal translucency scan shows NT of 4.2 mm at 12 weeks. She is anxious and asks: 'Will my baby have Down syndrome? What tests do I need?' To answer her — and to interpret the results of those tests — you need a thorough understanding of chromosomal aberrations.
WHY THIS MATTERS
Chromosomal disorders collectively affect ~1 in 160 live births and are a leading cause of early pregnancy loss (~50% of spontaneous abortions have chromosomal abnormalities). In India, the birth prevalence of Down syndrome is ~1 in 800; with the trend toward late first pregnancies in urban India, this number is rising. Klinefelter syndrome affects ~1 in 650 male births. Every clinician — not just geneticists — encounters these patients in paediatric OPD, neonatal units, fertility clinics, and antenatal care.
RECALL
Recall:
• How many chromosomes in a normal human somatic cell? In a gamete?
• What is non-disjunction and at which stage of cell division does it occur?
• What is meiosis I vs meiosis II? When does each happen in oogenesis vs spermatogenesis?
Human Karyotype and Chromosome Classification
Normal karyotype: 46 chromosomes = 22 pairs of autosomes + 1 pair of sex chromosomes
- Female: 46,XX | Male: 46,XY
Chromosome Classification (Denver system)
- Group A (1–3): largest; metacentric/submetacentric
- Group B (4–5): large; submetacentric
- Group C (6–12 + X): medium; submetacentric
- Group D (13–15): medium; acrocentric with satellites
- Group E (16–18): smaller; metacentric/submetacentric
- Group F (19–20): small; metacentric
- Group G (21–22 + Y): smallest; acrocentric with satellites
Karyotype notation examples
- 47,XX,+21 → Down syndrome (female)
- 45,X → Turner syndrome
- 47,XXY → Klinefelter syndrome
- 46,XY,del(5p) → Cri-du-chat syndrome
- 46,XX,t(9;22) → Philadelphia chromosome translocation
Numerical Aberrations
- Euploidy: correct number (46) — polyploidy is euploidy with extra complete sets (69,XXX = triploid)
- Aneuploidy: incorrect number, single chromosome affected
- Monosomy (2n−1): one chromosome missing → 45,X (Turner)
- Trisomy (2n+1): one chromosome extra → 47,XX,+21 (Down), 47,XXY (Klinefelter), 47,XY,+13 (Patau), 47,XY,+18 (Edwards)
- Tetrasomy, pentasomy: rare (XXXX, XXXXY)
- Mechanism: Non-disjunction during meiosis I (most common) or meiosis II; advanced maternal age increases risk
Structural Aberrations (require chromosome breakage)
- Deletion: loss of chromosome segment — del(5p) → Cri-du-chat; del(4p) → Wolf-Hirschhorn
- Duplication: segment repeated
- Inversion: segment inverted — pericentric (includes centromere) or paracentric (excludes centromere)
- Translocation: segment moves to another chromosome
- Reciprocal: mutual exchange between two non-homologous chromosomes
- Robertsonian: two acrocentric chromosomes fuse at centromere → 45 chromosomes total, BUT one chromosome carries two long arms → Robertsonian t(14;21) is the most common structural cause of Down syndrome (NOT age-related!)
- Isochromosome: identical arms on both sides of centromere — i(Xq) in Turner
- Ring chromosome: both ends of a chromosome join
Major Clinical Syndromes
Down Syndrome (Trisomy 21)
- Karyotype: 47,XX(or XY),+21 (95%); Robertsonian translocation (4%); mosaicism (1%)
- Maternal age effect: risk at 20y = 1:1500; at 35y = 1:350; at 45y = 1:25
- Features: flat facies, upward slanting palpebral fissures, epicanthal folds, single palmar crease, hypotonia, sandal gap between 1st–2nd toes, Brushfield spots, macroglossia, brachycephaly
- Cardiac defects (40–50%): AVSD (most common), VSD, ASD, PDA, Tetralogy of Fallot
- GI: duodenal atresia (double-bubble sign), Hirschsprung disease
- CNS: intellectual disability, increased Alzheimer's risk (amyloid precursor gene on chr 21)
- Leukaemia: 10–20× higher risk
Turner Syndrome (45,X)
- Only monosomy viable in humans; 45,X or mosaic 45,X/46,XX
- Features: short stature, webbed neck (pterygium colli), wide carrying angle (cubitus valgus), shield chest, wide-spaced nipples, lymphoedema of hands/feet at birth
- Streak gonads → primary amenorrhoea, infertility, absent secondary sex characteristics
- Bicuspid aortic valve (most common cardiac defect), coarctation of aorta
- Normal intelligence; may have learning difficulties in spatial tasks
- Treatment: GH for height, oestrogen replacement for puberty
Klinefelter Syndrome (47,XXY)
- Most common sex chromosome aneuploidy in males (1:650)
- Features often subtle until puberty: tall with long limbs (eunuchoid habitus), small firm testes, gynaecomastia, sparse body/facial hair
- Azoospermia → infertility (most common cause of male hypogonadism)
- Slightly lower IQ, language difficulties
- Increased risk: breast cancer, osteoporosis, type 2 diabetes
Patau Syndrome (Trisomy 13)
- Karyotype: 47,+13 or Robertsonian t(13q;14q)
- Severe malformations: holoprosencephaly, microphthalmia, cleft lip/palate, polydactyly, heart defects
- Median survival: 7–10 days; <10% survive beyond 1 year
Edwards Syndrome (Trisomy 18)
- Karyotype: 47,+18
- Rocker-bottom feet, overlapping fingers (index over middle), micrognathia, clenched fists, VSD
- Median survival: 5–15 days; ~10% survive to 1 year
SELF-CHECK
A. Reassure — a normal phenotype means no risk to offspring
B. Karyotype both parents to identify the carrier parent
C. Repeat amniocentesis at 20 weeks
D. Advise termination of pregnancy
Reveal Answer
Answer: A.
CLINICAL PEARL
Prenatal screening in Indian practice: The Indian FOGSI guidelines recommend combined first-trimester screening (NT + maternal serum PAPP-A + beta-hCG) at 11–13+6 weeks. A triple/quadruple test at 15–18 weeks is an alternative. If risk is ≥1:250, invasive testing (CVS or amniocentesis) is offered. Non-invasive prenatal testing (NIPT) by cell-free DNA is available in major cities but not universally funded. Under the MTP Act 2021, termination for foetal anomaly is permitted at any gestation with approval of a Registered Medical Practitioner and appropriate counselling.
REFLECT
KEY TAKEAWAYS
Core Take-Aways
- Normal human karyotype: 46 chromosomes (44 autosomes + XX or XY)
- Aneuploidy: non-disjunction → monosomy (45,X) or trisomy (+21,+13,+18,XXY)
- Down syndrome (trisomy 21): most common viable autosomal trisomy; flat facies, cardiac defects, intellectual disability; maternal age ↑ risk; Robertsonian translocation form is NOT age-related
- Turner (45,X): monosomy; webbed neck, short stature, primary amenorrhoea, streak gonads
- Klinefelter (47,XXY): tall, small testes, azoospermia, gynaecomastia
- Structural aberrations: deletions, duplications, inversions, translocations (reciprocal vs Robertsonian)
- Prenatal diagnosis: combined 1st trimester screen → CVS/amniocentesis → karyotype