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AN75.1-5 | Principles of Genetics, Chromosomal Aberrations & Clinical Genetics — Gate Quiz
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Which karyotype notation correctly represents a male with Down syndrome due to trisomy 21?
Correct. 47,XY,+21 = 47 total chromosomes (one extra), male (XY), extra chromosome 21.
Karyotype notation: [total number],[sex chromosomes],[aberration]. Trisomy = +chromosome. Monosomy = -chromosome. Male trisomy 21 = 47,XY,+21.
Standard karyotype notation: total chromosome number first, then sex chromosomes, then aberration. Trisomy 21 male = 47,XY,+21.
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Non-disjunction during meiosis I produces which of the following gametes (assuming a cell with 2n=4)?
Correct. Non-disjunction at meiosis I means homologous chromosomes fail to separate. One secondary oocyte/cell gets BOTH homologs, the other gets NONE for that pair — producing n+1 and n-1 gametes.
Meiosis I non-disjunction: both homologs → same cell → gametes: 2 get n+1, 2 get n-1. Meiosis II non-disjunction: sister chromatids don't separate → 1 gamete n+1, 1 gamete n-1, 2 normal gametes.
In meiosis I non-disjunction, both homologs go to the same secondary oocyte. After meiosis II, two gametes have n+1 (disomy) and two have n-1 (nullisomy) for that chromosome.
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A 16-year-old girl presents with primary amenorrhoea, short stature, and webbed neck. Her karyotype is 45,X. Which cardiac defect is MOST commonly associated with her condition?
Correct. Turner syndrome (45,X): bicuspid aortic valve is the most common cardiac defect (~30%), followed by coarctation of the aorta (~10%). These predispose to aortic dissection in adulthood.
Turner syndrome cardiac defects: bicuspid aortic valve (most common, ~30%), coarctation of aorta (~10%). Regular cardiac monitoring and echocardiography are essential throughout life due to risk of aortic dilatation/dissection.
Turner syndrome most commonly causes bicuspid aortic valve (30%) and coarctation of the aorta. VSD is the most common congenital heart defect overall but not specific to Turner syndrome.
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A 28-year-old man presents to a fertility clinic with infertility. He is tall (190 cm), has small firm testes, gynaecomastia, and sparse facial hair. His FSH and LH are elevated. Karyotype is 47,XXY. What is the MOST COMMON cause of azoospermia in this condition?
Correct. In Klinefelter syndrome, the extra X chromosome causes progressive hyalinisation and fibrosis of the seminiferous tubules → primary testicular failure → azoospermia. Elevated FSH/LH (hypergonadotrophic) confirms primary testicular failure.
Klinefelter syndrome = hypergonadotrophic hypogonadism: high FSH/LH (pituitary responding to failed testes), small firm testes, azoospermia. ICSI with testicular sperm extraction (TESE) may retrieve sperm in ~50% of cases.
Klinefelter causes PRIMARY testicular failure (hypergonadotrophic hypogonadism). The tubules degenerate → azoospermia. Elevated FSH reflects lack of inhibin B from Sertoli cells.
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A 42-year-old woman is pregnant for the first time. Her first-trimester combined screen risk is 1:50 for Down syndrome. She asks about the cause. The MOST COMMON mechanism for trisomy 21 is:
Correct. ~95% of Down syndrome is due to non-disjunction at meiosis I in the mother (primary oocytes arrested in prophase I can age over decades). This risk increases dramatically with maternal age.
Trisomy 21 causes: 95% meiosis I non-disjunction (age-related), 4% Robertsonian translocation (NOT age-related — important for young mothers), 1% mosaicism. Distinguish because Robertsonian recurrence risk differs based on which parent carries it.
The most common cause of trisomy 21 is maternal meiosis I non-disjunction (95%). Robertsonian translocation accounts for only ~4% and is NOT age-related.
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A 24-year-old woman has a child with Down syndrome. Her karyotype is 45,XX,t(14;21). Her husband's karyotype is normal. What is her recurrence risk for Down syndrome in future pregnancies?
Correct. When the MOTHER carries the Robertsonian translocation t(14;21), the recurrence risk for unbalanced offspring (Down syndrome) is approximately 10–15%. When the FATHER carries it, the risk is lower (~5%).
Robertsonian t(14;21) carrier: maternal carrier → ~10–15% Down syndrome risk; paternal carrier → ~5% risk. MUCH higher than age-related risk. Always karyotype both parents when a young mother has a Down syndrome child.
Robertsonian translocation carrier status overrides age-related risk. Maternal carrier: ~10–15% risk of Down syndrome offspring; paternal carrier: ~5%. This is NOT the population age-related risk.
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A 38-year-old woman at 11 weeks gestation has a nuchal translucency of 3.8 mm with a first-trimester combined screen risk of 1:100 for trisomy 21. She wants a definitive diagnosis. Which is the MOST APPROPRIATE next investigation?
Correct. For definitive diagnosis of chromosomal abnormality, invasive testing is required. CVS at 11–14 weeks provides a karyotype result within 2–3 weeks, allowing decisions earlier in pregnancy. Amniocentesis is the alternative after 15 weeks.
Definitive chromosomal diagnosis requires invasive testing: CVS (11–14 weeks, 0.5–1% miscarriage risk) or amniocentesis (15–20 weeks, 0.5% miscarriage risk). NIPT is screening only — high sensitivity/specificity but not diagnostic.
NIPT is a screening test (not diagnostic) with ~99% sensitivity but false positives occur. Definitive diagnosis requires invasive testing — CVS (11–14 weeks) or amniocentesis (15–20 weeks).
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A baby is born with a high-pitched cat-like cry, intellectual disability, microcephaly, and low birth weight. Which chromosomal aberration is responsible?
Correct. Cri-du-chat syndrome (French: cry of the cat) is caused by deletion of the short arm of chromosome 5 (del5p). The high-pitched cat-like cry is the diagnostic hallmark in neonates.
Cri-du-chat syndrome: del(5p), high-pitched cat-like cry (diagnostic in neonates due to laryngeal anomaly), microcephaly, widely-spaced eyes, intellectual disability. The cry lessens with age, making later diagnosis harder.
The cat-like cry (from laryngeal hypoplasia) is pathognomonic for Cri-du-chat syndrome — del(5p). Distinguish from Wolf-Hirschhorn (del4p) which shows 'Greek warrior helmet' facies.
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Approximately 50% of spontaneous first-trimester abortions have chromosomal abnormalities. Which type is MOST COMMON?
Correct. Autosomal trisomy is the most common chromosomal abnormality in spontaneous abortions (~50% of chromosomally abnormal abortuses), with trisomy 16 being the single most common. Most autosomal trisomies are lethal and rarely survive to term.
Chromosomal causes of early pregnancy loss: autosomal trisomy most common (~50% of chromosome abnormal SABs), most commonly trisomy 16. Only a few trisomies (21, 18, 13, sex chromosomes) survive to near-term.
In spontaneous abortions: autosomal trisomy (~50%) > monosomy X (~20%) > triploidy (~15%) > tetraploidy (~5%). Trisomy 16 is the most common single type in abortuses.
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A 29-year-old woman with no risk factors has NIPT showing high risk for trisomy 21 (positive predictive value quoted as 80%). She asks if her baby definitely has Down syndrome. What is the MOST ACCURATE response?
Correct. NIPT is a screening test with high sensitivity (~99%) and specificity, but a POSITIVE predictive value that varies with prior risk. In a LOW-risk 29-year-old, even with 80% PPV, 20% of positive results are false positives. Invasive testing (CVS/amniocentesis) is required before any irreversible decision.
NIPT has high sensitivity (~99%) and specificity (~99.9%) but PPV varies with prior risk. In low-risk patients, a positive NIPT has a lower PPV — around 45–80% for trisomy 21 depending on maternal age and baseline risk. Always confirm with invasive testing before irreversible decisions.
NIPT is a screening test — not diagnostic. A positive result means higher probability, not certainty. Confirmatory invasive testing is mandatory before counselling for termination.
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