The gene that causes sudden death

Researchers have identified a gene that causes arrhythmogenic right ventricle cardiomyopathy (ARVC) — a genetic disorder that predisposes seemingly healthy young people to cardiac arrest. The discovery is the result of an international collaboration headed by Professor Bongani Mayosi from the University of Cape Town.

For 20 years, Mayosi followed a South African family affected by ARVC that had experienced several cases of juvenile sudden death. Excluding all genetic causes known at the time, researchers from the Istituto Auxologico Italiano and the University of Pavia sequenced all the coding regions of the genome in two ill members of the family. The genetic mutation responsible for the disease in the family, CDH2, was narrowed down from more than 13,000 common genetic variants present in the two ill patients.

CDH2 is responsible for the production of Cadherin 2 or N-Cadherin, a key protein for normal adhesion between the cardiac cells. The gene’s discovery was validated by finding a second mutation on the same gene in another patient with ARVC from a different family. It was known from previous studies that genetically modified mice without this protein tend to suffer from malignant ventricular arrhythmias and sudden death.

The researchers said the identification of the gene helps to clarify the genetic mechanisms underlying ARVC, and also makes the early detection of ARVC possible in otherwise unsuspecting people. While the diagnostic clinical signs of the disease usually only become clear after many years, the study will make it possible to discover whether ARVC sufferers carry the CDH2 gene mutation. Other family members who are genetically affected can then be identified within a few weeks and preventive strategies can be started immediately.

“This is important news for families who have had a young family member suffer a sudden cardiac death, for them to know a genetic cause has been identified,” said Dr Guillaume Paré, who headed a team of investigators from Canada’s McMaster University and Hamilton Health Sciences.

“Our team was happy to contribute to the finding that a mutation in CDH2 is the underlying culprit in a portion of these patients. This will pave the way for preventative interventions and genetic counselling.”

The study was published in the journal Circulation: Cardiovascular Genetics.