Multiple genetic variations in sodium channel subunits in a case of sudden infant death syndrome
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Multiple genetic variations in sodium channel subunits in a case of sudden infant death syndrome. / Denti, Federico; Bentzen, Bo Hjorth; Wojciak, Julianne; Thomsen, Nancy Mutsaers; Scheinman, Melvin; Schmitt, Nicole.
I: Pacing and Clinical Electrophysiology, Bind 41, Nr. 6, 2018, s. 620-626.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 -
ID: 213283606