What is genetic penetrance?

Penetrance means “penetration.” In a genetic context, it refers to the probability that a mutated gene will actually lead to the disease. In the case of ALS, more than ten genes are known to cause the disease.

The first ALS gene was described in 1993: the superoxide dismutase 1 (SOD1) gene. Following the discovery of the SOD1 gene, it became apparent that nearly all individuals who carry a SOD1 mutation do in fact develop ALS at some point in their lives (high penetrance). Interestingly, reports emerged in the following years regarding other ALS genes (e.g., the C9orf72 gene) indicating that “carriers” do not develop ALS even into old age, despite having the mutation (low penetrance).

In addition to the genes that cause ALS, there are apparently several factors (other genes or environmental factors) that prevent a genetic trait (genetic mutation) from “manifesting” (reduced penetrance). Not only C9orf72, but also SOD1 and all other ALS-associated genes exhibit varying degrees of penetrance. When assessing the risk of disease in offspring (in patients with familial ALS), evaluating penetrance plays a crucial role and requires expert genetic counseling.