GeneticsTier 1Medical Sciences concept

Punnett square / recurrence risk calculations for autosomal dominant conditions

Core concept

	A	a
a	Aa affected	aa unaffected
a	Aa affected	aa unaffected

Each child, independently, 50% - sex-independent, and not affected by what happened to the previous children
- "They already have two affected children so the next is safe" is the trap. Meiosis has no memory.
Two affected heterozygotes (Aa x Aa) -> 3/4 affected, 1/4 AA homozygous - often lethal or much more severe (achondroplasia, FH)

Building the answer

```

Risk = P(inherits allele) x P(penetrance) x P(sex, if relevant) x P(parent is a carrier)

```

Multiply along a path, add across independent paths
BRCA1/2 - AD, 50% per child regardless of sex; males transmit and are themselves at risk (male breast, prostate, pancreas)
Reduced penetrance - multiply the 50% by the penetrance figure
- BRCA1 breast cancer penetrance ~65-75% by 80 yr, ovarian ~40%; BRCA2 ~45-55% and ~15%. The inheritance risk is 50%; the risk of disease is lower.
De novo rate - an affected child of unaffected parents may be a new mutation; recurrence risk for the sibs is then low but not zero (germline mosaicism ~1%)
Anticipation changes severity, not the 50%: in DM1 and HD, expansion is greater through the father for HD (juvenile HD is usually paternally transmitted) and through the mother for congenital DM1

Cascade testing - test first-degree relatives of the proband (each 50%), then extend outward; the familial variant is what is tested for, so the proband must be tested first
Reproductive options once a pathogenic variant is known
- Prenatal diagnosis (CVS ~11-13 wk, amniocentesis ~15-16 wk)
- Preimplantation genetic testing (PGT-M)
- Donor gamete, adoption, non-intervention
Predictive testing in an adult-onset untreatable condition (HD) requires formal genetic counselling, and is not offered to asymptomatic minors
Where surveillance changes outcome, test early: FAP (colectomy timing), MEN2 (prophylactic thyroidectomy), Lynch (colonoscopy from 25)

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