SA scientists collaborate in ‘sudden death’ gene mutation discovery

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GeneticMutation19Researchers at the University of Cape Town, through global collaboration, have identified the genetic mutation that is a major cause of sudden death among young people and athletes. Maryam Fish‚ Gasnat Shaboodien and Sarah Kraus make up the all-female UCT team that made the discovery.

The gene‚ called CDH2‚ is found in everyone, but a mutation causes a genetic disorder known as arrhythmogenic right ventricle cardiomyopathy (ARVC)‚ which increases the risk of heart disease and cardiac arrest. ARVC is a genetic disorder in which the heart tissue is replaced by fatty and fibrous tissue. This development causes rapid heart rhythm (cardiac arrhythmias) or rapid and erratic heart rhythm (ventricular fibrillation), which 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 minutes.

The discovery is the result of international collaboration that began 20 years ago. It was led by a South African team headed by Professor Bongani Mayosi, dean of UCT’s Faculty of Health Sciences, along with researchers of the Italian Auxologico Institute of Milan and the University of Pavia.

A team of investigators from the Population Health Research Institute of McMaster University and Hamilton Health Sciences, led by Dr Guillaume Paré, performed the genetic sequencing, as well as the bioinformatics analysis for the study. Dr Lia Crotti and Professor Peter Schwartz of the Italian Auxologico Institute of Milan sequenced all the coding regions of the genome.

“This is probably the biggest breakthrough in South African cardiology since Dr Chris Barnard’s first heart transplant,” said Mayosi. “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.”

According to research, cardiac deaths claim more than five lives every day in South Africa. In young 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. The discovery of the CDH2 gene will help clarify the genetic mechanisms underlying ARVC, and will make early detection of the disease possible in otherwise unsuspecting people.

“We learnt that it’s important if someone has the disease, intensive sports would be avoided. Athletes should be screened carefully. The disease can be treated, so that’s why it’s important to make the diagnosis early,” said Schwartz.

Often, the diagnostic clinical signs of the disease only become clear after many years. However, if a subject with ARVC is a carrier of a mutation of the CDH2 gene, other members of their family who are genetically affected can be identified and preventive strategies could be started. This may lead to a reduction of cases of sudden death in patients with the mutation, explained the researchers.

For almost 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, the Italian researchers sequenced all the coding regions of the genome in two ill members of the family.

According to Shaboodien, whole exome sequencing, the technique the researchers used to find the gene, was unheard of about seven to eight years ago. “In the old days it used to take two to three years to screen one gene … Suddenly with technology you are able to screen 19 000 genes within a matter of hours. We called it genetics on steroids.”

After the sudden death of a 22-year-old family member, cousins of the family member were identified as carriers of ARVC. “We sequenced all the genes in the human genome in two cousins who were affected‚” says Fish. “We then looked for common variants and had a list of 13 000, which we narrowed down through a series of filtering criteria to the CDH2 variant‚ which was the most likely causal variant in this family.”

The discovery of this gene was validated by finding a second mutation of the same gene in a number of unrelated individuals who also had ARVC.

“None of this would have been possible without the families and people willing to allow us to explore their families and screen them,” says Kraus. Currently the UCT research centre where the researchers worked is one of the few places in South Africa where genetic screening was done.

“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,” says Professor Glenda Gray, president and CEO of the South African Medical Research Council. “This collaborative research is what we relentlessly seek to fund, because it directly translates into finding ways to save lives in South Africa.”

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous condition caused by mutations in genes encoding desmosomal proteins in up to 60% of cases. The 40% of genotype-negative cases point to the need of identifying novel genetic substrates by studying genotype-negative ARVC families.
Methods and Results: Whole exome sequencing was performed on 2 cousins with ARVC. Validation of 13 heterozygous variants that survived internal quality and frequency filters was performed by Sanger sequencing. These variants were also genotyped in all family members to establish genotype–phenotype cosegregation. High-resolution melting analysis followed by Sanger sequencing was used to screen for mutations in cadherin 2 (CDH2) gene in unrelated genotype-negative patients with ARVC. In a 3-generation family, we identified by whole exome sequencing a novel mutation in CDH2 (c.686A>C, p.Gln229Pro) that cosegregated with ARVC in affected family members. The CDH2 c.686A>C variant was not present in >200 000 chromosomes available through public databases, which changes a conserved amino acid of cadherin 2 protein and is supported as the causal mutation by parametric linkage analysis. We subsequently screened 73 genotype-negative ARVC probands tested previously for mutations in known ARVC genes and found an additional likely pathogenic variant in CDH2 (c.1219G>A, p.Asp407Asn). CDH2 encodes cadherin 2 (also known as N-cadherin), a protein that plays a vital role in cell adhesion, making it a biologically plausible candidate gene in ARVC pathogenesis.
Conclusions: These data implicate CDH2 mutations as novel genetic causes of ARVC and contribute to a more complete identification of disease genes involved in cardiomyopathy.

Bongani M Mayosi, Maryam Fish, Gasnat Shaboodien, Elisa Mastantuono, Sarah Kraus, Thomas Wieland, Maria-Christina Kotta, Ashley Chin, Nakita Laing, Ntobeko BA Ntusi, Michael Chong, Christopher Horsfall, Simon N Pimstone, Davide Gentilini, Gianfranco Parati, Tim-Matthias Strom, Thomas Meitinger, Guillaume Pare, Peter J Schwartz, Lia Crotti


Notable cases of ARVC include Sevilla Football Club and Spanish international left wing Antonio Puerta who died from the condition, at the age of 22, in 2007, says a Cape Times report. Puerta collapsed and lost consciousness on the field from cardiac arrest. English professional footballer Matt Gadsby also died from the condition after collapsing on the pitch in 2006, aged 27.

According to estimates, sudden cardiac death claims the lives of more than five young South Africans a day. In Italy, about 50,000 people die suddenly every year.

The discovery of this gene will make the early detection of many people affected by ARVC possible and see a reduction of cases of sudden death, Schwartz is quoted in the report as saying. 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, Schwartz said.

“Often people die and then the diagnosis is made. There are patients who have palpitations, who faint and the diagnosis is made and they are alive, but all too often the diagnosis is made afterwards.” The mutation of the CDH2 gene is the indicator that a subject is genetically affected and allows the need to start preventive strategies such as lifestyle changes, Schwartz said.


The Times reports that the key to making the discovery was a new technique‚ whole exome sequencing‚ which analyses every gene in a human’s DNA. Shaboodien told Fish about the technique after finding out about it during a trip to Italy. “It took Maryam two to three years to screen one gene‚ then suddenly you could screen 19‚000 genes in a matter of hours using whole exome sequencing‚” said Shoobadien‚ who also leads the genetics team at UCT. “We called it genetics on steroids. Without this technique we would not have made discovery.”

Shaboodien said the discovery would help put South Africa on the map in the world of genetics‚ and showed “that we are capable of being on par with international researchers”.

The report says the clinical importance of the discovery meant early detection of unsuspecting people with ARVC was now possible. But Krause said testing for ARVC would not be easily accessible for most people‚ and the UCT research centre where they worked was one of the few places in South Africa where genetic screening was done.

“I think it’s important to understand there isn’t available (public) diagnostic screening in South Africa. In (the private sector) you can get your blood sent overseas to be screened‚” she said.

University of Cape Town material
Circulation: Cardiovascular Genetics abstract
Cape Times report
The Times report

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