Multiple genetic variations in sodium channel subunits in a case of sudden infant death syndrome.
BACKGROUND
Dysfunction of NaV 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.


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 NaV 1.5_1281X truncation revealed complete loss-of-function of the channel. Coexpression of NaV 1.5 with NaV β1b significantly increased INa density when compared to NaV 1.5 alone. The NaV β1b _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.
['Denti|Federico|F|', 'Bentzen|Bo Hjorth|BH|', 'Wojciak|Julianne|J|', 'Thomsen|Nancy Mutsaers|NM|', 'Scheinman|Melvin|M|0000-0002-3793-1867', 'Schmitt|Nicole|N|0000-0001-9482-9749']
D014644:Genetic Variation D006801:Humans D007223:Infant D008297:Male D062554:NAV1.5 Voltage-Gated Sodium Channel D010375:Pedigree D013398:Sudden Infant Death D062547:Voltage-Gated Sodium Channel beta-1 Subunit
sudden infant death syndrome SCN5A SIDS SCN1Bb patch-clamp electrophysiology