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AN74.1-4 | Patterns of Inheritance — Part 2

Multifactorial Inheritance: Polygenic Traits and the Threshold Model

Multifactorial inheritance (AN74.3) describes traits and diseases that result from the combined effects of multiple genes (polygenic component) interacting with environmental factors. Unlike single-gene disorders that follow clear Mendelian ratios, multifactorial conditions show continuous variation in the population and clustering in families without a predictable pattern. The polygenic model proposes that many genes, each with a small additive effect, contribute to a trait. The cumulative genetic contribution is termed the genetic liability. When environmental factors are added, the total liability forms a normal (Gaussian) distribution in the population.

Figure: Multifactorial Inheritance: Polygenic Traits and the Threshold Model

The threshold model proposed by Falconer explains how a continuously distributed liability can produce an all-or-none disease outcome. Below the threshold, individuals are unaffected; above the threshold, disease manifests. First-degree relatives of affected individuals share approximately 50% of their genes and therefore have a shifted liability distribution — their mean liability is closer to the threshold, resulting in a higher proportion exceeding it. This explains why the recurrence risk for first-degree relatives (typically 2-10%) is much higher than the population prevalence (typically 0.1-1%) but much lower than Mendelian ratios (25% or 50%).

Key characteristics distinguishing multifactorial from Mendelian inheritance include: (1) recurrence risk increases with the number of affected family members (unlike Mendelian risk which is fixed regardless of how many siblings are affected); (2) recurrence risk increases with the severity of the condition in the proband (a severely affected individual indicates higher genetic loading in the family); (3) when a multifactorial condition has unequal sex incidence, the recurrence risk is higher when the proband belongs to the less commonly affected sex (the Carter effect — e.g., pyloric stenosis is 5 times more common in males; when a female is affected, the recurrence risk for her siblings is higher because her family must carry a greater genetic load to exceed the higher female threshold); (4) recurrence risk decreases rapidly with decreasing degree of relationship; (5) concordance rates in monozygotic twins are significantly higher than in dizygotic twins, but less than 100% (indicating the environmental component).

Heritability (h²) is a statistical measure of the proportion of total phenotypic variance attributable to genetic factors in a given population. It ranges from 0 (entirely environmental) to 1 (entirely genetic). Twin studies are the classic method for estimating heritability: h² ≈ 2 × (MZ concordance − DZ concordance). Important caveats: heritability is a population statistic, not an individual predictor; it applies only to the specific population and environment studied; and high heritability does not mean a trait is immutable (height has h² ≈ 0.8 but has increased dramatically with improved nutrition).

Clinically important multifactorial conditions relevant to Indian practice include: neural tube defects (NTDs — anencephaly and spina bifida, with an incidence of 4-11 per 1,000 births in India, much higher than the global average of 1-2 per 1,000; periconceptional folic acid supplementation reduces risk by 50-70%); type 2 diabetes mellitus (India is the 'diabetes capital of the world' with over 100 million affected individuals; genetic susceptibility interacts with the 'thrifty genotype' hypothesis, urbanisation, dietary changes, and physical inactivity); coronary artery disease (Indians develop CAD a decade earlier than Western populations, with a complex interplay of genetic factors including lipoprotein(a) levels, environmental factors including tobacco use, diet, and the metabolic syndrome); congenital heart defects (the most common birth defect category, with prevalence of 8-12 per 1,000 live births); cleft lip with or without cleft palate (incidence varies by ethnicity, approximately 1 in 700-1,000 births in India); and essential hypertension (affecting approximately 30% of urban and 15% of rural adult Indians).

Pedigree Construction and Genetic Counselling Applications

Constructing and interpreting pedigree charts (AN74.2) is an indispensable skill for clinical genetics. A systematic approach to pedigree analysis involves five steps.

Figure: Pedigree Construction and Genetic Counselling Applications

Step 1: Gather family history systematically. Record at least three generations. For each family member, document: age, health status, age at diagnosis of relevant conditions, cause and age at death, consanguinity, ethnicity, and whether genetic testing has been performed. In Indian practice, enquire specifically about consanguinity — uncle-niece marriages, first-cousin marriages, and same-gotra marriages in some communities.

Step 2: Draw the pedigree using standard symbols. Place the oldest generation at the top. Males are represented by squares, females by circles. A horizontal line connects mating partners; a vertical line descends to their offspring, who are arranged left to right in birth order. Filled (shaded) symbols indicate affected individuals. A diagonal line through a symbol indicates the person is deceased. A dot inside a circle indicates a known female carrier of an X-linked condition. A double horizontal line between partners indicates consanguinity. The proband (index case or consultand) is marked with an arrow labelled 'P'.

Step 3: Identify the pattern of inheritance. Systematically ask: Does the trait appear in every generation (vertical) or skip generations (horizontal)? Are males and females equally affected? Is there male-to-male transmission (rules out X-linked)? Is there consanguinity (suggests AR)? Does severity increase across generations (anticipation — suggests trinucleotide repeat disorder)? Are all children of affected mothers affected (mitochondrial)?

Step 4: Calculate recurrence risks. Once the inheritance pattern is established, use Mendelian ratios modified by penetrance, carrier probability calculations (Bayesian analysis for complex situations), and population carrier frequencies (Hardy-Weinberg equilibrium: p² + 2pq + q² = 1, where q² is the disease frequency and 2pq is the carrier frequency) to determine the probability that a specific individual is a carrier or that a future pregnancy will be affected.

Step 5: Communicate findings clearly. Genetic counselling should be non-directive — present the risks and options without imposing decisions. In Indian practice, this is particularly important given cultural sensitivities around consanguinity, prenatal diagnosis, and termination of pregnancy. The Medical Termination of Pregnancy (MTP) Act 2021 in India permits termination up to 20 weeks for substantial risk of physical or mental abnormality in the foetus (up to 24 weeks with approval by two registered medical practitioners for special categories).

Hardy-Weinberg equilibrium is essential for calculating carrier frequencies. For an AR condition with disease frequency q² = 1/10,000, q = 1/100, and the carrier frequency 2pq ≈ 2 × 1 × 1/100 = 1/50. This means that for every affected individual, there are approximately 200 carriers in the population. For common conditions like sickle cell trait in tribal populations of central India (carrier frequency 10-30%), the Hardy-Weinberg calculation predicts disease frequency of q² = (0.15)² ≈ 2.25% — consistent with observed frequencies.

Bayesian analysis combines prior probabilities (based on pedigree position) with conditional probabilities (based on additional information such as test results or number of unaffected children) to calculate posterior probabilities. For example, a woman whose brother has Duchenne muscular dystrophy has a prior probability of 2/3 of being a carrier (her mother is an obligate carrier, so each daughter has a 1/2 chance of inheriting the X^d allele, but since we know the mother must be a carrier, the prior for each daughter is 2/3 if no other information is available). If this woman has three unaffected sons, the conditional probability of this occurring if she is a carrier is (1/2)³ = 1/8, while if she is not a carrier it is 1. Bayesian calculation then revises her carrier risk downward from 2/3 to approximately 2/11.

Clinical Genetics Disorders: Detailed Case Studies

The NMC competency AN74.4 specifically requires knowledge of three conditions: achondroplasia, cystic fibrosis, and vitamin D-resistant rickets. Having covered achondroplasia and cystic fibrosis in Part 1, here we present clinical vignettes illustrating genetic reasoning.

Figure: Clinical Genetics Disorders: Detailed Case Studies

Clinical Vignette 1 — Achondroplasia: A 3-year-old boy is brought to the paediatrics OPD in a government hospital in Rajasthan. His parents are of normal stature. He shows rhizomelic shortening of limbs (upper arms and thighs disproportionately short), macrocephaly with frontal bossing, midface hypoplasia with a depressed nasal bridge, trident hand configuration (inability to approximate the middle and ring fingers), and exaggerated lumbar lordosis. His intelligence and speech development are age-appropriate. Radiographs show short, broad tubular bones with metaphyseal flaring, a narrow spinal canal, and small iliac wings with horizontal acetabular roofs. This presentation is classic achondroplasia. Genetic testing reveals the G380R mutation in FGFR3. Since both parents are unaffected, this is a de novo mutation. Counselling points: (1) the child's risk of transmitting achondroplasia to his own offspring is 50%; (2) recurrence risk for the parents' future pregnancies is very low (approximately 1% — attributable to gonadal mosaicism); (3) potential complications to monitor include foramen magnum stenosis (risk of cervicomedullary compression), obstructive sleep apnoea, recurrent otitis media, and spinal stenosis in adulthood.

Clinical Vignette 2 — Cystic Fibrosis: A 14-month-old girl from Kerala presents with failure to thrive, recurrent lower respiratory tract infections, and steatorrhoea (bulky, foul-smelling, oily stools). Her parents are first cousins. Sweat chloride test shows 82 mmol/L (normal <30, borderline 30-59, diagnostic ≥60). CFTR gene sequencing reveals homozygosity for a missense mutation common in the Indian subcontinent. Management includes pancreatic enzyme replacement therapy (PERT), fat-soluble vitamin supplementation (A, D, E, K), chest physiotherapy and mucolytics, and prophylactic antibiotics. The consanguinity in this family is a classic risk factor for AR conditions. Cascade screening of extended family members is recommended.

Clinical Vignette 3 — Vitamin D-Resistant Rickets (XLH): A 4-year-old girl from Hyderabad presents with progressive bowing of the legs despite adequate vitamin D intake and sun exposure. Investigations show low serum phosphate (1.8 mg/dL, normal 4-7), elevated alkaline phosphatase, normal calcium, normal 25-hydroxy vitamin D, and elevated FGF23 levels. Her father is short (155 cm) with residual leg bowing. This X-linked dominant condition means the father transmitted the mutant PHEX gene to his daughter (he passes his X to all daughters). Treatment involves oral phosphate supplementation and calcitriol (active vitamin D). The key distinguishing feature from nutritional rickets — extremely common in Indian children — is the phosphate wasting and failure to respond to vitamin D supplementation alone.

Additional AR disorders common in India: (1) Sickle cell disease — HbS mutation (Glu6Val in beta-globin gene), carrier frequency 10-30% in tribal populations of Maharashtra, Madhya Pradesh, Chhattisgarh, Odisha, and Jharkhand; clinical features include vaso-occlusive crises, chronic haemolytic anaemia, and splenic sequestration; (2) Beta-thalassaemia major — multiple mutations in the beta-globin gene, carrier frequency 3-17% across different Indian communities; presents with severe anaemia, hepatosplenomegaly, and skeletal deformities from extramedullary haematopoiesis; (3) Wilson disease — ATP7B gene mutations, relatively common in India due to consanguinity; presents with hepatic, neurological, and psychiatric manifestations; Kayser-Fleischer rings on slit-lamp examination are pathognomonic.