Multiple genetic variations in sodium channel subunits in a case of sudden infant death syndrome

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Dysfunction of Na(V)1.5 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.

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.

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 Na(V)1.5_1281X truncation revealed complete loss-of-function of the channel. Coexpression of Na(V)1.5 with Na(V)1b significantly increased I-Na density when compared to Na(V)1.5 alone. The Na(V)1b _V268I variant abolished this I-Na density increase. Moreover, it shifted the activation curve toward more depolarized potentials.

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
Original languageEnglish
JournalPacing and Clinical Electrophysiology
Issue number6
Pages (from-to)620-626
Publication statusPublished - 2018

    Research areas

  • patch-clamp electrophysiology, SCN5A, SCN1Bb, SIDS, sudden infant death syndrome

ID: 213283606