Scientists discover gene responsible for AVSD


A team of researchers from the UK, with help from researchers in Germany, Canada, Belgium and the Netherlands, have identified a gene that plays an important role in the formation of congenital heart defects. The gene, with the name NR2F2, indirectly controls the development of different organs by promoting or blocking transcription factor genes.

In a multi-stage process, researchers examined samples from 125 patients with an atrioventricular septum defect (AVSD) for conspicuous changes to their DNA. This was when the research team from the Wellcome Trust Sanger Institute in Cambridge, UK made an interesting discovery. The group, led by Dr. Saeed Al Turki, Dr. Marc-Phillip Hitz and Dr. Matthew Hurles, used exome sequencing to analyse all the DNA’s protein coding information and found changes to the NR2F2 gene.

Just a small section of the entire human genome is actually analysed during exome sequencing. The exome makes up only about 1.5 percent of the entire human DNA, but it is estimated that it is responsible for more than 85 percent of all genetic disorders. Dauntingly, the exome still contains 30 million base pairs that need to be analysed and interpreted; these huge amounts of data represent a major challenge.

After this discovery, the results were further reviewed using DNA samples from the biomaterial bank at Germany’s National Register for Congenital Heart Defects. As a next step, Dr. Sabine Klaassen at Charité Berlin and her research group examined the NR2F2 gene in the DNA of families (father-mother-child) in which the child has a heart condition. After sequencing the exomes of more than one hundred patients and their families, researchers could confirm that the NR2F2 gene was also mutated in other heart defects, such as aortic stenosis, coarctation of the aorta and hypoplastic left heart syndrome.

For their work, the researchers needed as many biomaterial samples from patients with specific heart defects as possible; a difficult task, because many heart defects are exceedingly rare. This is why the National Register for Congenital Heart Defects, supported by the German Federal Ministry of Education and Research (BMBF), collects blood and tissue samples from patients in a biomaterial bank and makes them available to scientists. Nearly 50,000 patients participate in the register, and 3,500 patients have already provided a DNA sample.  In this way, they all support medical advancement.

Al Turki S, Manickaraj AK, Mercer CL, Gerety S, Hitz MP, Lindsay S, D'Alessandro LCA, Swaminathan J, Bentham J, Arndt AK, Low J, Breckpot J, Gewillig M, Thienpont B, Abdul-Khaliq H, Harnack C, Hoff K, Kramer HH, Schubert S, Siebert R, Toka O, Cosgrove C, Watkins H, Lucassen AM, O'Kelly IM, Salmon AP, Bu'Lock FA, Granados-Riveron J, Setchfield K, Thornborough C, Brook JD, Mulder B, Klaassen S, Bhattacharya S, Devriendt K, FitzPatrick DF, UK10K, Wilson DI, Mital S, Hurles ME.
Rare variants in NR2F2 cause congenital heart defects in humans
Am J Hum Genet. 2014 Apr 3;94(4):574-85.


PD Dr. Sabine Klaassen
Department of Pediatrics, Division of Cardiology

Experimental and Clinical Research Center (ECRC)
Charité - Universitätsmedizin Berlin
Tel: +49 30 450-540656 und +49 30 9406-3319