Autosomal dominant and recessive inheritance, penetrance and carrier risk

At a glance

• Autosomal dominant (AD): one abnormal copy is enough. Each child of an affected parent has a 50% risk. Vertical transmission, both sexes, male-to-male transmission possible.
• Autosomal recessive (AR): two abnormal copies needed. Two carrier parents have a 25% risk of an affected child each pregnancy. Usually one generation (horizontal), consanguinity raises the risk.
• Real pedigrees are blurred by reduced penetrance, variable expressivity, de novo variants and germline mosaicism.
• Paper 1 asks for numbers. Know Hardy-Weinberg, the 2/3 rule and how to combine probabilities.

Autosomal dominant

Feature	Detail
Transmission	Vertical; every affected person has an affected parent, unless de novo or non-penetrant
Sexes	Equal; male-to-male transmission excludes X-linked
Risk to child	50% per pregnancy, independent each time
Mechanism	Haploinsufficiency, dominant negative or gain of function
Homozygotes	Often more severe (homozygous FH: LDL above 13 mmol/L, coronary disease in childhood)

Examples with their own notes: Marfan syndrome, neurofibromatosis type 1, ADPKD, Huntington disease, BRCA1 and BRCA2, Lynch syndrome and familial adenomatous polyposis. Familial hypercholesterolaemia (about 1 in 250) is the commonest serious AD disease.

What blurs a dominant pedigree

• Reduced penetrance. BRCA1 carriers have about a 70% lifetime breast cancer risk, so some carriers never develop cancer. Huntington alleles of 36 to 39 CAG repeats are incompletely penetrant. A skipped generation suggests non-penetrance in the middle person.
• Variable expressivity. In NF1, one family member has a few café-au-lait macules and another a plexiform neurofibroma. Same variant, different severity.
• Age-dependent penetrance. ADPKD cysts and Huntington chorea appear in adulthood, so a negative examination at 20 doesn't exclude the genotype.
• De novo variants. About 80% of achondroplasia and 50% of NF1. Parents are unaffected, recurrence risk in siblings is low (about 1%).
• Germline mosaicism. A parent with the variant in some gametes but not in blood. It explains two affected children of unaffected parents with a "de novo" dominant condition.
• Anticipation. Earlier onset or more severe disease in successive generations in repeat expansion disorders such as myotonic dystrophy.

Autosomal recessive

Feature	Detail
Transmission	Usually affected siblings with unaffected parents
Parents	Obligate heterozygous carriers
Risk per pregnancy	25% affected, 50% carrier, 25% non-carrier
Unaffected sibling	2/3 chance of being a carrier
Consanguinity	Raises risk, especially for rare diseases. First cousins share 1/8 of their genes
Mechanism	Usually loss of function; half the enzyme is enough

Compound heterozygotes carry two different pathogenic variants in the same gene, one on each copy (common in CF). Testing parents confirms the variants are in trans (on opposite copies), not both on one chromosome.

Common adult AR conditions: cystic fibrosis, haemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency, thalassaemia and sickle cell disease.

Pitfall: HFE C282Y homozygosity is about 1 in 200 in people of northern European ancestry, but the HealthIron study in Melbourne found iron-overload-related disease in only 28.4% of homozygous men and 1.2% of women. Low penetrance, not a dominant pattern, explains the patchy family history.

Worked examples

Example 1: carrier frequency from incidence (Hardy-Weinberg)

With alleles p (normal) and q (disease), genotype frequencies are p², 2pq and q².

• CF incidence in northern European populations is about 1 in 2,500, so q² = 1/2,500 and q = 1/50.
• Carrier frequency 2pq ≈ 2 × 1/50 = 1/25 (because p is close to 1).

Example 2: risk to a sibling's child

Sarah is healthy. Her brother has CF. Her partner has no family history and northern European ancestry.

• Sarah's carrier risk: 2/3.
• Partner's carrier risk: 1/25.
• If both are carriers, risk of an affected child: 1/4.
• Combined: 2/3 × 1/25 × 1/4 = 1/150 per pregnancy.

Example 3: residual risk after a negative carrier test (Bayes)

The partner has a carrier test that detects 90% of CF variants in his ancestry group, and it is negative.

	Carrier	Not a carrier
Prior	1/25 = 0.04	0.96
Probability of a negative test	0.10	1
Joint	0.004	0.96
Posterior	0.004 / 0.964 ≈ 1 in 241

Sarah's risk of an affected child is now 2/3 × 1/241 × 1/4 ≈ 1 in 1,450. If Sarah herself tests positive, replace 2/3 with 1, giving about 1 in 960.

Example 4: dominant with reduced penetrance

A woman's father carries a pathogenic BRCA2 variant. She is untested. Her chance of carrying it is 50%. If she tests negative for the known familial variant, her risk returns to the population level. A negative test in a relative without a known familial variant is uninformative.

Australian practice

• Reproductive carrier screening for CF (CFTR), spinal muscular atrophy (SMN1) and fragile X (FMR1) has been Medicare-funded since 1 November 2023 (item 73451, once per lifetime, for people pregnant or planning pregnancy; partner under item 73452 when the person tested first carries a CFTR or SMN1 variant). RANZCOG recommends offering information about carrier screening to everyone planning pregnancy or in the first trimester, whatever their family history or ancestry.
• Expanded panels covering hundreds of AR and X-linked genes are available privately. Most couples at increased risk have no family history.
• Cascade testing of relatives once a familial pathogenic variant is known is the most efficient way to find carriers of AD conditions such as FH and Lynch syndrome. Genetic counselling comes first.

How it's tested

• Pedigree interpretation: male-to-male transmission, skipped generations, affected siblings with healthy parents.
• Calculations: carrier frequency from incidence, the 2/3 rule, risk to a sibling's child, residual risk after a negative test.
• Explaining a surprising pedigree: non-penetrance, germline mosaicism, de novo variant, uniparental disomy.

Pitfalls

• Pitfall: the 2/3 carrier risk applies only to unaffected siblings. Including the affected outcome gives the wrong answer of 1/2.
• Pitfall: risk is independent for each pregnancy. Having one affected child doesn't make the next three unaffected.
• Pitfall: a skipped generation in a dominant pedigree usually means non-penetrance, not recessive inheritance.
• Pitfall: carrier frequency differs by ancestry. Use the right population figure, and remember test detection rates differ too.
• Pitfall: a negative test for a relative is informative only when the familial variant is known.