Sudden infant death syndrome–associated mutations in the sodium channel beta subunits

BackgroundApproximately 10% of sudden infant death syndrome (SIDS) cases may stem from potentially lethal cardiac channelopathies, with approximately half of channelopathic SIDS involving the NaV1.5 cardiac sodium channel. Recently, NaV beta subunits have been implicated in various cardiac arrhythmias. Thus, the 4 genes encoding NaV beta subunits represent plausible candidate genes for SIDS.ObjectiveThis study sought to determine the spectrum, prevalence, and functional consequences of sodium channel beta-subunit mutations in a SIDS cohort.MethodsIn this institutional review board–approved study, mutational analysis of the 4 beta-subunit genes, SCN1B to 4B, was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing of DNA derived from 292 SIDS cases. Engineered mutations were coexpressed with SCN5A in HEK 293 cells and were whole-cell patch clamped. One of the putative SIDS-associated mutations was similarly studied in adenovirally transduced adult rat ventricular myocytes.ResultsThree rare (absent in 200 to 800 reference alleles) missense mutations (β3-V36M, β3-V54G, and β4-S206L) were identified in 3 of 292 SIDS cases. Compared with SCN5A+β3-WT, β3-V36M significantly decreased peak INa and increased late INa, whereas β3-V54G resulted in a marked loss of function. β4-S206L accentuated late INa and positively shifted the midpoint of inactivation compared with SCN5A+β4-WT. In native cardiomyocytes, β4-S206L accentuated late INa and increased the ventricular action potential duration compared with β4-WT.ConclusionThis study provides the first molecular and functional evidence to implicate the NaV beta subunits in SIDS pathogenesis. Altered NaV1.5 sodium channel function due to beta-subunit mutations may account for the molecular pathogenic mechanism underlying approximately 1% of SIDS cases.