Genetics of VHL

VHL is a hereditary disease that is caused by pathogenic variants (disease-causing changes) in the VHL gene. This disease is estimated to affect approximately 1 in 30,000-50,000 people worldwide.

All individuals have two copies of the VHL gene, one inherited from each parent. VHL is an autosomal dominant disease, meaning someone must have a pathogenic variant (disease-causing change) in one copy of the VHL gene in order to have an increased risk of developing tumors. Both men and women are equally likely to have and pass on VHL. This disease is considered highly penetrant, meaning that most individuals with VHL will experience one or more tumors over their lifetime.

A person who has a parent or sibling with VHL has a 50% chance of also having VHL. However, someone may still have a chance of having VHL if a more distant relative, such as an aunt, uncle, cousin or grandparent, has VHL. Genetic testing for the VHL gene performed on a blood (or saliva) sample is the most conclusive way of determining if someone has VHL.

While the majority of VHL cases are due to a pathogenic variant that was passed down from a parent, approximately 20% of individuals with VHL have a new (de novo) pathogenic variant in the VHL gene that was not inherited from either parent. A de novo pathogenic variant occurs either in an egg or sperm cell, or very early in an embryo’s development. If present in the egg or sperm, the VHL pathogenic variant will be present in all of the cells of the embryo. However, if this occurs later in the development of the embryo, only some cells will have this VHL pathogenic variant, which is called mosaicism.

If a clinical diagnosis of VHL is suspected, but there is no known family history, genetic testing can help confirm the diagnosis.