Incomplete penetrance

Last update: April 14, 2016

Typical of autosomal dominant transmission

penetranza incompletaWhat’s incomplete penetrance? When is it more common?

Sometimes a patient harboring a disease-causing genetic mutation remains totally asymptomatic for their whole life. This is due to a genetic phenomenon known as incomplete penetrance. Incomplete penetrance occurs mainly in autosomal dominantly inherited disorders. The definition of penetrance is consistent with the percentage of subjects harboring a disease-causing mutation and showing clinical symptoms. Most genetic disorders show a penetrance of 100%.

Repeat expansion disorders

Besides autosomal dominant disorders caused by typical single nucleotide variations or deletions/insertions, incomplete penetrance can be found also in repeat expansion disorders. 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 fully penetrant alleles (Warby SC et al, PMID: 20301482).

Age of onset

Several disorders characterized by incomplete penetrance also show late onset of symptoms in the adult age. The more a mutated patient remain asymptomatic during the years, the more likely is that he/she will never develop the disorder at all.

Association with certain types of mutations

As said above, incomplete penetrance is typical of autosomal dominant disorders, which are often caused by genetic mutations with particular biological characteristics. These can be gain-of-function mutations or mutations causing haploinsufficiency or mutations affecting proteins which are crucial in certain tissues/organs, but not in others. This one last type of mutation are also the cause of another well-known genetic phenomenon: variable expressivity. Incmplete penetrance as well as variable expressivity are thought to be influenced by genetic, epigenetic and/or environmental factors (i.e. lifestyle habits, living environment, or the presence of other genetic variants which can modulate the effect of the disease-causing mutation).

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

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