New genetic cause identified for congenital heart arrhythmia

Scientists at The Ohio State University Dorothy M. Davis Heart and Lung Research Institute have identified a new genetic cause for congenital heart arrhythmia. The results of their research are published online by the Proceedings of the National Academy of Sciences (PNAS).

The mechanism is due to defects in the regulation of the primary sodium channel, which controls the flow of sodium ions across the heart cell membrane. When these channels don't work properly, it promotes abnormal heart rate (arrhythmia) and symptoms of heart failure.

"The mechanism of disease was unexpected," said Hassan Musa, a research scientist in Ohio State's Department of Physiology and Cell Biology and first author of the publication. "As a field, we are beginning to identify genetic variants that alter the sodium channel's association with essential regulatory proteins. However, in this case, we were surprised by the impact of this gene variant on the regulation of the sodium channel by a protein called FGF12."

Musa and the team examined genes from a 27 year old man who had suffered sudden cardiac arrest while moving boxes at work. Further In addition to the cardiac arrest, tests showed the man also has atrial fibrillation. Doctors implanted a defibrillator which has appropriately fired several times to save the man's life.

"Because of this man's cardiac arrest at a young age, as well as his family history of sudden cardiac death, our team in the Inherited Arrhythmia Clinic had a high suspicion for an inherited arrhythmia disease, so we conducted genetic testing for known arrhythmia genes," said Amy Sturm, licensed genetic counselor and a co-author on the research. "This identified a novel mutation previously undescribed in the sodium channel SCN5A gene. Mutations in SCN5A are associated with several hereditary cardiovascular diseases, so we knew it was a strong candidate for his and his family's arrhythmia condition."

Further screening of the man's family showed his mother, sister and young niece also have the SCN5A gene variant.

The team tested the impact the mutation had on signaling proteins (fibroblast growth factor homologous factors - FHFs) that regulate sodium channels and found it blocked the proteins from binding and caused abnormal function consistent with human arrhythmia.

"It's the first evidence of human arrhythmia based on gene variants that block FHFs," said Peter Mohler, director of the Davis Heart and Lung Research Institute and corresponding author of the study. "This will need to be tested further as more regulatory proteins are associated with cardiac cell function."