Expressivity

Variable expressivity can occur in all phenotypes, including in signs and symptoms of genetic conditions. Many conditions present differently in different people: some may have relatively mild symptoms of a condition, while others’ symptoms are debilitating.

In many cases, it is not known why one person with a condition experiences mild symptoms while someone else’s are severe. Some of the possible reasons are listed below.

• A different genetic variant is responsible for the condition, resulting in fewer or less severe symptoms. For example, there are multiple different variants (in the same or different genes) that cause dilated cardiomyopathy.
• Different people can have different background genetic variation. For example, one person may have a protective variant in a different gene while someone else has a variant that amplifies the condition.
• Lifestyle and environmental factors can have an effect. For example, increased exposure to carcinogens will increase a person’s chance of developing cancer (irrespective of genotype), while reduced exposure may prevent someone at genetic risk of developing cancer from doing so (although there is no certainty in this).
• Biological sex can be a factor. For example, while men can develop breast cancer, they cannot develop ovarian cancer. In other situations, particular hormones may increase or decrease a person’s chance of developing a particular condition.
• Sometimes a variant that results in a condition occurs in some cells in the body but not all of them. This is known as mosaicism, and often results in milder symptoms.

Understanding that a condition may present differently in different family members can be important in determining inheritance patterns and interpreting results from genomic testing. For example, parents of a child with an unexplained syndrome may have their genomes sequenced alongside the affected child’s. In these situations, the parents are assumed to be unaffected by the condition affecting their child because they are not showing symptoms; for that reason, any variants shared by both parents and the child would be ruled out as part of the child’s genomic diagnosis. However, it is important to be absolutely certain that the parents are indeed unaffected by the child’s condition, and do not simply have mild symptoms as a result of variable expressivity.

• Many conditions present differently in different people because of variable expressivity.
• In many cases, it is not clear why a condition presents differently in different individuals.
• It is important to recognise variable expressivity when determining who in a family is affected by a condition and who is not, because this affects variant interpretation.