Novel sodium channel mutation identified in a Finnish family – a new piece in the puzzle of genetic cardiac arrhythmias
Numerous mutations in genes encoding cardiac ion channels and ion channel interacting proteins have been identified as the cause of inherited arrhythmias. Major heterogeneity in both the genetic background and the phenotypic features of these diseases exists.
A Finnish-Swiss research group has now found the cause of a disease called exercise-induced polymorphic ventricular arrhythmia in a large Finnish family. In this family, there were originally 13 family members diagnosed of having this type of arrhythmia and several others got the diagnosis during the follow-up.
The key persons involved were M.D. Ph.D. Heikki Swan from Helsinki University Hospital, Heart and Lung Center and M.D. Ph.D. Elisabeth Widén from FIMM. The researchers had studied this family for more than 10 years but the cause of the disease had remained unknown despite sequencing the most likely candidate genes. The group decided to utilize the exome sequencing methodology and samples from eight affected family members were sequenced at the FIMM Technology Centre. Based on these results, the disease causing mutation was revealed.
The cause of the symptoms was shown to be a novel missense mutation in one of the known arrhythmia genes, SCN5A, the product of which is a sodium channel that is abundant in cardiac muscle. After identifying the mutation, the research group was able to show by functional studies that the mutation changed the gating properties of this channel and induced hyperactivation.
Previously, mutations in SCN5A have been shown to be the cause of a broad spectrum of clinical cardiac phenotypes such as Brugada syndrome and atrial fibrillation. This inherited exercise-induced polymorphic ventricular arrhythmia is another interesting piece in the puzzle of genetic cardiac arrhythmias.
"This finding is especially important for the studied family since it enables presymptomatic diagnostics. The family members not carrying the mutation can now be discharged from the long-term follow-up that otherwise would be necessary", Dr. Heikki Swan said. "SCN5A will also be added to the panel of genes screened when genetic testing for catecholaminergic polymorphic ventricular tachycardia is performed."
Swan H, Amarouch MY, Leinonen J, Marjamaa A, Kucera JP, Laitinen-Forsblom PJ, Lahtinen AM, Palotie A, Kontula K, Toivonen L, Abriel H, Widen E. A Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias Circ Cardiovasc Genet. 2014 Sep 10. pii: CIRCGENETICS.114.000703. [Epub ahead of print]. PubMed PMID: 25210054.