INCOMPLETE PENETRANCE: A TYPICAL FEATURE OF AUTOSOMAL DOMINANT INHERITANCE

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What's incomplete penetrance? In which diseases incomplete penetrance is more frequent?

Sometimes a genetic disease does not become clinically evident (i.e. the patient remains totally asymptomatic) even when the patient has a disease-causing mutation. This phenomenon is called incomplete penetrance and it is not rarely observed in some autosomal dominantly inherited genetic disorders. Penetrance is a term that defines the percentage of subjects with a disease-causing mutation who really shows clinical signs of the disease (i.e. are clinically affected).

Sometimes it is the mutation type to cause incomplete penetrance. This can be the case of several disorders caused by repeat expansion. In Huntington disease, for instance, alleles with 36-39 repeats are classified as "incomplete penetrance alleles", whereas alleles with 40 repeats or more are classified as alleles with full penetrance (Warby SC et al, PMID: 20301482).

Sometimes penetrance is linked to the age of onset of the disease. In autosomal dominant disorders with typical onset in the adult age the penetrance rate tends to increase as the patient ages (i.e. the more the patient gets older, the higher the chance that clinical signs and symptoms are showing up). Conversely, for an old patient without clinical disease it is easier to think that he is not carrying the disease-causing mutation (especially if he's already gone beyond the typical range of clinical onset). 

Incomplete penetrance is typical of autosomal dominant diseases, which are often caused by genetic mutations with particular biological characteristics. Mutations that cause dominant traits are often gain-of-function mutations or mutations that cause haploinsufficiency or affect proteins which are crucial for the proper functioning of some tissues/organs, but not others. Reason, the latter, which is also the basis of variable expressivity (in fact, those factors that can drive variable expressivity in the clinical manifestation of the disease could also be the ones that can lead to the extreme pole of complete absence of signs and symptoms, i.e. incomplete penetrance). Such factors are likely to be genetic, epigenetic and/or environmental.

However, it must be mentioned that there are also autosomal dominant diseases where penetrance is complete or almost complete. Let's consider, for example, tuberous sclerosis, in which penetrance is estimated to be 100% (Northrup H, 201, PMID: 20301399).

Related articles:

• HAPLOINSUFFICIENCY, DOMINANT NEGATIVE EFFECT AND AUTOSOMAL DOMINANT INHERITANCE