SEMA3A – Brugada syndrome

SEMA3A has been proposed as a minor contributor to Brugada syndrome, an autosomal dominant arrhythmogenic disorder marked by ventricular arrhythmias and risk of sudden cardiac death. A comprehensive American College of Medical Genetics and Genomics (ACMG)–guided review of 133 rare variants in non-SCN5A genes found six conclusively pathogenic variants across four genes (SLMAP, SEMA3A, SCNN1A, SCN2B), including a single heterozygous SEMA3A variant classified as pathogenic in one Brugada syndrome proband, without reported segregation or functional cardiac assays (PMID:30821013).

Given only one definitively pathogenic SEMA3A variant in a single case and absence of familial co-segregation or mechanistic studies in cardiomyocytes, the current genetic evidence for SEMA3A in Brugada syndrome is limited. No in vitro electrophysiological or animal model data demonstrate that SEMA3A disruption alters myocardial sodium currents or repolarization. Further segregation analyses and cardiac functional assays are needed to determine whether SEMA3A variants have clinical utility in Brugada syndrome diagnosis and risk stratification. Key Take-home: routine testing of SEMA3A in Brugada syndrome remains premature pending additional genetic and functional validation.

References

• Human Mutation • 2019 • Genetic interpretation and clinical translation of minor genes related to Brugada syndrome. PMID:30821013

Evidence Based Scoring (AI generated)