Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

Abstract

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases1–3. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10−68; rs9388451, P = 5.1 × 10−17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10−14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10−81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction4–7 can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development8. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

Impact of clinical and genetic findings on the management of young patients with Brugada syndrome

“…By contrast, none of the 17 genotype-negative patients, suffered a LTA event. Thus, in our cohort the presence of a SCN5A mutation may be necessary, but is insufficient on its own for the development of LTA 23,24 . These results should, however, be treated cautiously due to the low number of patients and the high prevalence of SCN5A mutations.…”

Genetic and Phenotypic Characterization of Community Hospital Patients With QT Prolongation

“…Furthermore, many of the patients with a pathogenic or likely pathogenic variant had QT prolongation exceeding the values that one may expect from a specific QT‐prolonging factor, favoring these patients when considering patients for genetic testing. A role for common variants on QT interval and arrhythmia has been demonstrated, but they still have limited clinical utility and their contribution in this cohort has not been analyzed 28, 29…”

The role of genetic testing in unexplained sudden death

“…Recent evidence has also supported an oligogenic inheritance pattern. 82 The most commonly affected gene is the SCN5A gene (approximately 20% of BrS cases, BrS1 83 ). More than 300 mutations of SCN5A have been described 84 leading to loss of function because of a reduction in the amplitude of the sodium channel current by reduced expression and/or altered voltage-gating properties.…”