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Snapshot: What Does Incomplete Penetrance Mean?

Incomplete penetrance is a characteristic of a wide range of genetic diseases, including hereditary forms of neurodegenerative disease, heart disease, and cancer. In short, it means that individuals carrying a disease-causing mutation may not necessarily develop disease symptoms. “Penetrance” refers to the proportion of individuals carrying the disease-causing mutation that develops disease phenotypes. A penetrance of 100% means that all individuals with the disease-causing mutation will develop symptoms. In comparison, a penetrance of 70% is referred to as incomplete and means that only 70% of individuals with the disease-causing mutation will develop disease symptoms.

Triplet Repeat Diseases and Incomplete Penetrance

Triplet repeat diseases are a group of rare hereditary diseases caused by expansions of three repeating nucleotides in the DNA. Examples of triplet repeat disorders include Huntington’s disease and many hereditary ataxias. The length of the expansion often dictates disease onset and progression, but the cut-off size between developing and not developing disease is often not well defined. In Huntington’s disease, for instance, unaffected individuals carry less than 35 repeats in their HTT gene. Repeats of 36-39 are considered incomplete penetrant as not all individuals will develop disease symptoms. Repeats equal to or more than 40 are highly penetrant with a high likelihood to develop disease. Many repeat expansion disorders such as SCA2, SCA7, SCA8, SCA17, and SBMA are incomplete penetrant at certain expansion lengths, contributing to variable reports of disease cut-off in research studies.

Incomplete Penetrance and Variable Expression

It is worth noting that incomplete penetrance differs from variable expression of a disease. Variable expression means that the disease symptoms are present, but the severity levels vary between individuals. Incomplete penetrance and variable expression are caused by various factors, including the environment, genetics, and lifestyle choices. Diseases can also be both variable and incomplete penetrant in nature, making it difficult to provide an accurate diagnosis. Understanding how a patient’s environment and genetics affect disease severity and penetrance is therefore an active area of research.

If you would like to learn more about Incomplete Penetrance, take a look at these resources by MedlinePlus and the NHS Genomics Education Programme.