The genetics of BHD

BHD is caused by mutations in the Folliculin gene on chromosome 17, also known as FLCN for short.

It is an autosomal dominant disorder, which means that a mutation in just one of your two copies is enough for the disease to develop. Genes are the blueprints for proteins, and BHD patients usually have mutations that mean one of their Folliculin genes doesn’t code for a fully working protein. This means that BHD patients have half the amount of working Folliculin protein as someone without BHD.

In very rare cases, you might have a brand new mutation (also called a “de novo” mutation), meaning that you are the first person in your family to have BHD. However, there has only been one reported case of this, so it is far more likely that you have inherited BHD from one of your parents, even if they don’t know they have it. It is therefore also possible that any blood-relatives from that side of the family also has BHD (e.g. your siblings, grandparents, aunts, uncles, cousins).

If you have BHD, each of your children has a 50% chance of inheriting BHD (see diagram below).

BHD symptoms don’t usually appear until after the age of twenty, so genetic testing is not usually done until the age of 18. However, there have been four reported cases of children aged 7, 14 and 16 with BHD getting a collapsed lung, so you should be aware of this risk.

If you are worried about your children, you should talk to your doctor or a genetic counsellor about if and when they should be tested for BHD. If you have BHD but do not already have children, and would like some information on the options available to you, please read our section on family planning.

Having only half the amount of Folliculin protein can lead to the skin and lung symptoms of BHD – this is known as haploinsufficiency. In contrast, kidney tumours are believed only to form when the second copy of the Folliculin gene in a cell also becomes mutated (a “second-hit”), resulting in no Folliculin protein being produced. Random mutations can happen in any gene or cell, and are accumulated over time throughout the body. As BHD patients are born with one mutated copy of the Folliculin gene, only a single random mutation in the second copy of the Folliculin gene in a kidney cell has to develop for a tumour to grow. Although it can take decades for these second-hit Folliculin mutations to occur, the requirement for only one such random mutation in every kidney cell results in an increased likelihood of multiple tumours over time.

Publication date: December 2014
Review date: December 2017