SCN5A – Familial Atrial Fibrillation

A heterozygous SCN5A gain-of-function variant, c.5381A>G (p.Tyr1794Cys), was identified in all eight members of a three-generation family, of whom three adults presented with paroxysmal atrial fibrillation and prolonged QTc intervals, consistent with autosomal dominant inheritance and cosegregation of the variant with atrial fibrillation (3 affected relatives) (PMID:18929331).

Patch-clamp studies of p.Tyr1794Cys expressed in HEK293 cells revealed slowed onset of inactivation, a negative shift in steady-state inactivation, and increased sustained inward sodium current—biophysical defects that support a gain-of-function mechanism underlying arrhythmogenesis (PMID:11410597).

References

• Heart rhythm • 2008 • A mutation in the sodium channel is responsible for the association of long QT syndrome and familial atrial fibrillation. PMID:18929331
• The Journal of biological chemistry • 2001 • Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. PMID:11410597

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