Gene Discovered Can Cause Sudden Cardiac Death

Guillaume Paré, associate professor at McMaster University’s DeGroote School of Medicine, "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 counseling."

Inherited forms of cardiomyopathy often cause sudden cardiac arrest death in young people under the age of 35. In ARVC, heart tissue is replaced by fatty and fibrous tissue. This process encourages the development of cardiac arrhythmias such as tachycardia and ventricular fibrillation, which cause loss of consciousness and cardiac arrest. In the case of ventricular fibrillation, without a ready electrical defibrillation, it causes sudden death in a few minutes.

For 20 years, Prof. 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, the Italian researchers sequenced all the coding regions of the genome in two ill members of the family. The mutation responsible for the disease in the family 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 (N-Cadherin), a key protein for normal adhesion between the cardiac cells. The gene's discovery was validated by finding a second CDH2 mutation in another patient with ARVC from a different family. Also, it was known from previous studies that genetically modified mice without this protein tend to have malignant ventricular arrhythmias and sudden death.

Identifying the gene helps to clarify genetic mechanisms underlying ARVC, and makes early detection of ARVC possible in otherwise unsuspecting people. Often, the diagnostic clinical signs of the disease only become clear after many years. Now, if someone with ARVC is a carrier of a defective CDH2 mutation, other family members who are genetically affected can be quickly identified and preventive strategies initiated immediately.

The study, by Mayosi BM et al, was published March 8, 2017, in the journal Circulation: Cardiovascular Genetics.