Key result
NaV1.5_1281X and NaVβ1b_V268I variants abolish in vitro INa density but are insufficient alone for sudden death.
Why the study?
Dysfunction of NaV1.5 encoded by SCN5A accounts for about half of channelopathic SIDS cases, but the combined effect of multiple sodium channel gene variants in SIDS is unclear.
Case Report (n=2)
Genetic variation in both the sodium channel and its modifiers can alter channel function and may contribute to sudden unexplained death in childhood, though incomplete penetrance is possible.
May inform genetic evaluation in childhood sudden death but should not yet alter management; leaves open the contribution of modifier variants and penetrance.
Background Dysfunction of NaV1.5 encoded by SCN5A accounts for approximately half of the channelopathic SIDS cases. We investigated the functional effect of two gene variants identified in the same patient, one in SCN5A and one in SCN1Bb. The aim of the study was to risk stratify the proband's family. Methods The family was referred for cardiovascular genetic evaluation to assess familial risk of cardiac disease. Functional analysis of the identified variants was performed with patch‐clamp electrophysiology in HEK293 cells. Results A 16‐month‐old healthy boy died suddenly in the context of nonspecific illness and possible fever. Postmortem genetic testing revealed variants in the SCN5A and SCN1Bb genes. The proband's father carries the same variants but is asymptomatic. Electrophysiological analysis of the NaV1.5_1281X truncation revealed complete loss‐of‐function of the channel. Coexpression of NaV1.5 with NaVβ1b significantly increased INa density when compared to NaV1.5 alone. The NaVβ1b _V268I variant abolished this INa density increase. Moreover, it shifted the activation curve toward more depolarized potentials. Conclusions Genetic variation of both sodium channel and its modifiers may contribute to sudden unexplained death in childhood. However, the asymptomatic father suggests that genetic variation of these genes is not sufficient to cause sudden death or clinically detectable SCN5A phenotypes.
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Denti et al. (2018) conducted a case report in Sudden infant death syndrome (SIDS) (n=2). SCN5A and SCN1Bb gene variants (NaV1.5_1281X and NaVβ1b_V268I) vs. Wild-type channels (in vitro) was evaluated on Functional effect of gene variants on INa density and activation. The NaV1.5_1281X and NaVβ1b_V268I variants caused complete loss-of-function and abolished INa density increase in vitro, though the asymptomatic father suggests they are insufficient alone to cause sudden death.
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