Core concept1 exam ›
```
Risk of clinical disease
= P(parent 1 transmits mutant) x P(parent 2 transmits mutant) x PENETRANCE
```
- Penetrance is a multiplier applied last, after the Mendelian genotype risk
- Genotype risk = probability of inheriting two mutant alleles
- Penetrance = probability that this genotype produces the phenotype
- The commonest error is stopping at the genotype probability and calling it the disease risk
Key detail
Worked
- Both parents known carriers, penetrance 40%
- genotype risk 1/4 -> 1/4 x 0.4 = 10% clinical disease
- Genotype and phenotype risks are different numbers and the question specifies which it wants
- Affected parent (aa) x carrier parent (Aa), penetrance 60%
- genotype risk 1/2 -> 30%
- Carrier status of a parent uncertain -> add that probability into the chain
- unaffected sib of an affected child = 2/3 carrier (Bayes: AA excluded from 1AA:2Aa)
- x general-population carrier frequency 2q x 1/4 x penetrance
Why penetrance is incomplete
- Modifier genes (HFE penetrance modified by iron-loss and metabolic cofactors)
- Environment / exposure - only the exposed express it (G6PD deficiency needs an oxidant, MCAD needs fasting, porphyria needs a precipitant)
- Sex-limited or sex-influenced expression (haemochromatosis: menstrual loss protects women)
- Age-dependent penetrance - the figure quoted must specify the age ("penetrance by 70 years")
- Ascertainment bias inflates published penetrance - families were found because they were severely affected; population-based estimates are consistently lower
Adjacent terms
- Expressivity - severity among those affected, not whether they are affected
- Pseudodominance - an AR condition appearing in consecutive generations when carrier frequency is high or there is consanguinity
Clinical relevance
- The counselling number is the clinical-disease risk, not the genotype risk - state both, and state the age the penetrance figure refers to
- HFE C282Y homozygosity is the model: genotype ~1/200, but biochemical penetrance high while clinical penetrance is only ~10-30% in men and <10% in women - the reason population screening is not done
- Low penetrance is why predictive testing in an asymptomatic relative can generate anxiety without changing management, and why VUS results must not be acted on
- Where penetrance is high and intervention effective, testing changes outcomes (MEN2 -> prophylactic thyroidectomy; Lynch -> colonoscopy); where it is low, surveillance may be all that is offered
Correlations
- Hardy-Weinberg equilibrium and carrier frequency
- Punnett square recurrence risk in autosomal dominant conditions
- Pedigree analysis - incomplete penetrance and generation skipping
- HFE mutations and haemochromatosis genotype-phenotype
- Complex/polygenic disease genetics
4 of 4 sections written · drafted 2026-09-04