16.5 Genetics and Health: Inheritance, Screening & Counseling
Key Takeaways
- Human inheritance follows Mendelian patterns — autosomal dominant (each child of an affected parent has a 50% risk; e.g. Huntington disease), autosomal recessive (25% recurrence risk; e.g. thalassaemia, sickle cell, CF) and X-linked recessive (carrier mothers, affected sons; e.g. haemophilia, Duchenne muscular dystrophy).
- India carries a high burden of haemoglobinopathies — β-thalassaemia carrier frequency ~3–17% by region and sickle cell disease concentrated in central/tribal belts; carrier screening and prenatal diagnosis form the public-health prevention strategy.
- Population genetic screening tiers are carrier screening (pre-conception/at-risk couples), prenatal diagnosis (CVS 10–13 weeks, amniocentesis 15–20 weeks) and newborn screening (congenital hypothyroidism, G6PD, sickle cell where prevalent).
- Periconceptional folic acid supplementation (400 µg/day, ≥4 weeks pre-conception) reduces neural tube defect recurrence and first occurrence — the single most cost-effective genetic primary-prevention intervention.
- Non-directive genetic counseling presents recurrence risks and reproductive options without coercion; consanguinity increases autosomal recessive disease burden and warrants carrier screening.
16.5 Genetics and Health: Inheritance, Screening & Counseling
High-Yield Core Concept: The PSM syllabus lists Genetics and Health as a distinct topic. CMS questions test the recurrence-risk percentages for Mendelian disorders, the Indian public-health burden of haemoglobinopathies, and the screening tests available at each stage of the reproductive lifecycle.
1. Modes of Inheritance
| Pattern | Recurrence risk | Hallmarks | Examples |
|---|---|---|---|
| Autosomal dominant | 50% | Vertical transmission, both sexes affected, variable penetrance | Huntington disease, familial hypercholesterolaemia, achondroplasia, Marfan |
| Autosomal recessive | 25% | Horizontal (sibs), often no family history, consanguinity ↑ risk | β-thalassaemia, sickle cell, cystic fibrosis, phenylketonuria |
| X-linked recessive | 50% of sons of a carrier mother | Affected males, carrier females; no male-to-male transmission | Haemophilia A/B, Duchenne muscular dystrophy, red-green colour blindness |
| X-linked dominant | 50% | Both sexes affected, often lethal in males | Hypophosphatamic rickets |
| Mitochondrial | All children of affected mother | Maternal transmission only | Leber hereditary optic neuropathy, MELAS |
| Multifactorial | Empirical (~3–5%) | Threshold + environment | NTD, diabetes, hypertension, cleft lip/palate |
Chromosomal disorders: Down syndrome (trisomy 21, 1:700, ↑ maternal age), Edwards (18), Patau (13), Turner (45,X), Klinefelter (47,XXY).
2. Burden of Genetic Disease in India
Haemoglobinopathies dominate the Indian genetic burden:
- β-thalassaemia — carrier frequency 3–17% (mean ~3–4%), higher in Sindhi, Punjabi, Gujarati, Bengali communities; ~10,000 thalassaemia major births/year.
- Sickle cell disease — concentrated in central, eastern and tribal belts (Odisha, Chhattisgarh, Madhya Pradesh, Maharashtra, Gujarat); the S allele reaches carrier frequency >20% in some tribal groups.
- Haemophilia — estimated 1:10,000 males (A) and 1:50,000 (B).
Consanguinity, common in south Indian and some Muslim communities, increases autosomal recessive disease risk.
3. Population Genetic Screening
Three-tier screening aligns with the reproductive lifecycle:
| Tier | When | Test | Purpose |
|---|---|---|---|
| Carrier screening | Pre-conception / antenatal | Hb electrophoresis/HPLC for at-risk couples; mutation panel | Identify carriers to offer prenatal diagnosis |
| Prenatal diagnosis | 10–20 weeks | CVS 10–13 wks, amniocentesis 15–20 wks, NIPT/cffDNA | Diagnose affected fetus; reproductive choice |
| Newborn screening | Birth / 48–72 h | Heel-prick (TSH/T4 for CH, G6PD, sickle cell where prevalent) | Early treatment of treatable inherited disease |
Prenatal diagnostic techniques are governed by the PCPNDT Act 1994 — usable only for detecting genetic/metabolic/chromosomal disorders, never sex determination.
4. Genetic Counseling
A communication process conveying recurrence risk and reproductive options. Core principles:
- Non-directive — present risks and options, respect autonomy.
- Pre-conception ideally — most choices exist before pregnancy.
- Recurrence-risk figures: AR 25%, AD 50%, X-linked recessive 50% of carrier mother's sons, multifactorial empirical ~3–5%.
- Address psychosocial, ethical and cultural dimensions; offer support groups.
Indications: advanced maternal age (≥35), previous affected child, family history of genetic disease, parental consanguinity, abnormal prenatal screening/ultrasound, recurrent pregnancy loss.
5. Primary & Secondary Prevention
Primary prevention (before disease occurs):
- Periconceptional folic acid — 400 µg/day starting ≥4 weeks before conception through first trimester reduces neural tube defect risk by up to 70%; 4 mg/day for women with a prior NTD-affected pregnancy.
- Avoid teratogens (alcohol, certain drugs, radiation), rubella vaccination pre-conception, optimise diabetes control.
Secondary prevention (early detection):
- Prenatal screening — first-trimester combined screen (NT + PAPP-A + free β-hCG), quadruple test, anomaly scan at 18–20 weeks.
- Newborn screening for congenital hypothyroidism, G6PD deficiency, sickle cell disease (in high-prevalence states).
Thalassaemia prevention programme (national model): awareness → carrier screening → prenatal diagnosis → option of termination of affected fetus — implemented through regional thalassaemia centres.
6. Common Chromosomal & Multifactorial Disorders in Practice
CMS genetics questions favour a handful of high-yield chromosomal and multifactorial conditions:
| Disorder | Karyotype / basis | Key features |
|---|---|---|
| Down syndrome | Trisomy 21 (95%), translocation (4%), mosaic (1%) | Flat face, epicanthal folds, single palmar crease, AV canal, duodenal atresia, hypothyroidism, ↑ maternal age risk |
| Edwards syndrome | Trisomy 18 | Clenched fists, rocker-bottom feet, low birth weight, short life expectancy |
| Patau syndrome | Trisomy 13 | Cleft lip/palate, polydactyly, holoprosencephaly |
| Turner syndrome | 45,X | Short stature, webbed neck, streak ovaries, coarctation of aorta, primary amenorrhoea |
| Klinefelter syndrome | 47,XXY | Tall, gynaecomastia, small firm testes, infertility, learning difficulties |
Prenatal screening integrates first-trimester combined test (NT + PAPP-A + free β-hCG, performed 11–13+6 weeks), the quadruple test (15–22 weeks: αFP, hCG, uE3, inhibin-A), and the anomaly scan at 18–20 weeks. A raised αFP flags open neural tube defects and abdominal wall defects; a low αFP with high hCG raises Down syndrome risk. Diagnostic confirmation is by CVS or amniocentesis with karyotype/microarray, governed by the PCPNDT Act.
Multifactorial inheritance applies to common conditions with a polygenic-plus-environment basis — neural tube defects, cleft lip/palate, congenital heart disease, diabetes and hypertension. Recurrence risk is empirical (~3–5%) and counselling combines family-history assessment with primary prevention (e.g. periconceptional folic acid for NTD).
Key Takeaways for the CMS Candidate
- Recurrence risk by inheritance pattern: AD 50%, AR 25%, X-linked recessive 50% of sons of a carrier — the most testable numbers.
- India's genetic burden is dominated by haemoglobinopathies; the prevention model is carrier screening + prenatal diagnosis.
- Periconceptional folic acid 400 µg/day is the single most cost-effective primary-prevention intervention.
- Genetic counseling is non-directive and ideally pre-conception.
- Prenatal diagnostic techniques are regulated by the PCPNDT Act (genetic diagnosis only, never sex determination).
Both parents are healthy carriers of cystic fibrosis (autosomal recessive). What is the recurrence risk of an affected child in each pregnancy?
Which public-health intervention most directly provides primary prevention of neural tube defects at the population level?