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Why can the severity of an autosomal dominant disease differ among family members?

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BRCA2 tumor suppressor gene on chromosome 13 — human genetic disease Photomicrograph of the *BRCA2* tumor suppressor gene on chromosome 13 of the human genome. Inactivation of this growth-regulating gene is associated with a higher risk of developing breast cancer.

The severity of an autosomal dominant disease can differ among family members due to a phenomenon known as variable expressivity. This refers to the wide range of clinical symptoms and degrees of severity that can manifest in different individuals who carry the same disease-causing gene.12

Several factors contribute to these variations in phenotypic expression:

Modifying Genes: The presence of other genes, including epistatic genes, can mask or influence the expression of the primary disease gene. An epistatic gene may subordinate the disease gene, causing some individuals to show only partial symptoms or, in cases of nonpenetrance, no symptoms at all.13
Environmental Factors: External influences play a significant role in how a genetically induced disease manifests. The individual's environment can interact with their genetic constitution to exacerbate or mitigate the severity of the condition.4
Epigenetic Modifications: Chemical changes to DNA or associated proteins, such as methylation, can regulate gene expression by activating or silencing specific sequences. These modifications can influence whether a gene is expressed and to what degree, contributing to differences in clinical outcomes even among those with the same mutation.56