Discovery of New Gene That Causes Sudden Death in Young Athletes Interview with:
Lia Crotti, MD, PhD

Department of Cardiovascular, Neural and Metabolic Sciences
San Luca Hospital
IRCCS Istituto Auxologico Italiano What is the background for this study?

Response: Sudden cardiac death in one of the major cause of death in Western Countries and among the causes of these deaths in young people under the age of 35, inherited forms of cardiomyopathy have a prominent role. Among these cardiomyopathies, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) plays a major role. In ARVC, the heart tissue is replaced by fatty and fibrous tissue. This process encourages the development of life-threatening arrhythmias, such as ventricular fibrillation, that causes a cardiac arrest and sudden death in few minutes without a ready device to shock the heart. Intense physical activity favors the progression of the disease and arrhythmias are frequently triggered by adrenergic activation: those are the reason why young athletes with this disease are at high risk. What are the main findings?

Response: We identified a novel gene responsible for ARVC studying a South African three generation family. We sequenced all the exonic part of the genome of two affected subjects and the genetic mutation responsible for the disease in the family was narrowed down from more than 13,000 rare genetic variants present in the two sick subjects.  This is the CDH2 gene, responsible for the production of Cadherin 2 or N-Cadherin, a key protein for normal adhesion between the cardiac cells. The discovery of this gene has been validated by finding a second mutation on the same gene in another patient with ARVC belonging to a different family. It was already known from previous studies that genetically modified mice and in which this protein is absent in the heart tend to have malignant ventricular arrhythmias and sudden death. What should readers take away from your report?

Response: The importance of the discovery is twofold, and has both a scientific and a clinical impact.  From a scientific perspective it helps to clarify the genetic mechanisms underlying ARVC, contributing to a more complete identification of the disease genes involved in cardiomyopathy. Furthermore, this discovery  will open the possibility to develop new and more specific treatments in future.

The clinical impact is straightforward. This finding means that it will become possible to make the diagnosis of ARVC earlier and in a larger number of patients. It is known that in several patients the clinical diagnosis is made late or too late. Now whenever in the screening for ARVC a mutation will be found in CDH2 gene, it will be possible within 2-3 weeks to screen the entire family and all the carriers of the disease will be identified before any symptom. This will allow the institution of preventive treatment resulting in lives saved What recommendations do you have for future research as a result of this study?

Response: I would encourage centers following patients with ARVC to screen the CDH2 gene.

Furthermore, functional studies aimed at understanding better the mechanisms linking CDH2 mutations and ARVC will be very useful to advance our knowledges. Thank you for your contribution to the community.


Bongani M. Mayosi et al.Identification of Cadherin 2 (CDH2) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation: Cardiovascular Genetics, March 2017 DOI: 1161/CIRCGENETICS.116.001605

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on March 21, 2017 by Marie Benz MD FAAD