Medical researchers, through a global collaboration, have identified a new gene that is a major cause of sudden death among young people and among athletes. The gene, called CDH2, causes Arrhythmogenic Right Ventricle Cardiomyopathy (ARVC), a genetic disorder that predisposes young people to cardiac arrest.

At the forefront of this research is 30 year old Maryam Fish from Lansdowne who led an all-female team of researchers at the University of Cape Town‚ along with Gasnat Shoobadien and Sarah Krause‚ who made the discovery with researchers from Italy.

“We sequenced all the genes in the human genome in two cousins who were affected‚” said Fish‚ explaining that the cousins were identified after a 22-year-old relative died suddenly.

“We then looked for common variants and had a list of 13‚000 which we narrowed down through a series of filtering criteria until we got the CDH2 variant‚ which was the most likely causal variant in this family.”

According to country estimates, sudden cardiac death claims the lives of more than 5 young South Africans per day. In Italy, amongst the whole population, about 50,000 people die suddenly every year. In young people, like amongst South Africans, an inherited form of disease of the heart muscle (cardiomyopathy) appears to have a prominent role in the cause of sudden death that is related to cardiac disease.

“This is probably the biggest breakthrough in South African cardiology since Dr Chris Barnard’s first heart transplant”, said Professor Bongani Mayosi, Dean of the Faculty of Health Sciences at the University of Cape Town (UCT).

“This discovery is a first in the world – on our soil – and will permit the diagnosis and possible targeted treatment of heart muscle disease in the future.”

In ARVC, the heart muscle tissue is replaced by fatty and fibrous tissue. This process encourages the development of an abnormal heart rhythm (cardiac arrhythmias) such as rapid heart rhythm or rapid and erratic heart rhythm (ventricular fibrillation), that causes loss of consciousness and cardiac arrest. In the case of ventricular fibrillation, without a ready device to shock the heart, it causes sudden death in a few minutes.

The importance of the discovery is twofold, and has both scientific and clinical impact. On the one hand it helps to clarify the genetic mechanisms underlying ARVC, contributing to a more complete identification of the disease genes involved in cardiomyopathy. On the other, it makes possible the early detection of many unsuspecting people who are affected by ARVC.

“When pioneering medical researchers make discoveries such as this, it enables us to innovate to find easy ways to detect the gene or diagnose ARVC and find ways to prevent sudden death in young South Africans” said Professor Glenda Gray, president & CEO of the South African Medical Research Council (SAMRC).

“This collaborative research is what we relentlessly seek to fund, because it directly translates into finding ways to save lives in South Africa.”

Often the diagnostic clinical signs of the disease become clear only after many years. If a subject with ARVC is a carrier of a mutation of the gene CDH2, it means that the subject is at a higher risk of cardiac disease.

Researchers say all people carry the gene however, the mutation of the CDH2 gene is the indicator that someone is genetically affected and allows the need to start preventive strategies such as lifestyle changes to ensure that the subject lives a healthy life. This may lead to a reduction of cases of sudden death in patients with this mutation.

This discovery, published today in the prestigious journal Circulation: Cardiovascular Genetics, was made from a South African family affected by ARVC and is as a result of an international collaboration which began 15 years ago. Excluding all genetic causes so far known, Dr Crotti and Professor Peter Schwartz of the Italian Auxologico Institute (Auxo) of Milan, sequenced all the coding regions of the genome in two sick persons of the family.

The genetic mutation responsible for the disease in the family was narrowed down from more than 13,000 common 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 cardiac tend to have malignant ventricular arrhythmias and sudden death.