TY - JOUR

T1 - Multiple genetic variations in sodium channel subunits in a case of sudden infant death syndrome

AU - Denti, Federico

AU - Bentzen, Bo Hjorth

AU - Wojciak, Julianne

AU - Thomsen, Nancy Mutsaers

AU - Scheinman, Melvin

AU - Schmitt, Nicole

PY - 2018

Y1 - 2018

N2 - BackgroundDysfunction 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. MethodsThe 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. ResultsA 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. ConclusionsGenetic 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

AB - BackgroundDysfunction 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. MethodsThe 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. ResultsA 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. ConclusionsGenetic 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

KW - patch-clamp electrophysiology

KW - SCN5A

KW - SCN1Bb

KW - SIDS

KW - sudden infant death syndrome

U2 - 10.1111/pace.13328

DO - 10.1111/pace.13328

M3 - Journal article

C2 - 29572929

VL - 41

SP - 620

EP - 626

JO - PACE - Pacing and Clinical Electrophysiology

JF - PACE - Pacing and Clinical Electrophysiology

SN - 0147-8389

IS - 6

ER -