Genome Researchers Identify Mutation Linked to Cardiac Disorder

ARVC is a life-threatening disease that often afflicts (although is not exclusive to) young male athletes. Mutations within the desmosome - molecular complexes of cell adhesion proteins and linking proteins that attach the cell surface adhesion proteins to intracellular keratin cytoskeletal filaments - are the main cause of ARVC. The mutations cause the replacement of heart muscle 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. The current incidence within the population is accepted as 1/10,000 however it is thought that 1/200 may have a mutation that may predispose to ARVC.

Investigators from Canada, South Africa, and Italy collaborated to perform a whole exome sequencing study on two cousins from a South African family affected by ARVC that had experienced several cases of juvenile sudden death over a period of 20 years. After eliminating more than 13,000 common genetic variants, a mutation in the gene cadherin 2 (CDH2), was identified in the two cousins.

CDH2, also called N-cadherin, named originally for its role in neural tissue, was later was found to be active in cardiac muscle and in cancer metastasis. CDH2 is a transmembrane, homophilic glycoprotein belonging to the calcium-dependent cell adhesion molecule family. These proteins have extracellular domains that mediate homophilic interactions between adjacent cells, and C-terminal, cytoplasmic tails that mediate binding to catenins, which in turn interact with the actin cytoskeleton.

"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 contributing author Dr. Guillaume Paré, associate professor of pathology and molecular medicine at McMaster University.

"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 March 8, 2017, online edition of the journal Circulation: Cardiovascular Genetics.