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Mol Genet Genomic Med DOI:10.1002/mgg3.1309

The role of sodium channels in sudden unexpected death in pediatrics.

Publication TypeJournal Article
Year of Publication2020
AuthorsRochtus, AM, Goldstein, RD, Holm, IA, Brownstein, CA, Pérez-Palma, E, Haynes, R, Lal, D, Poduri, AH
JournalMol Genet Genomic Med
Pagese1309
Date Published2020 May 25
ISSN2324-9269
Abstract

BACKGROUND: Sudden Unexpected Death in Pediatrics (SUDP) is a tragic event, likely caused by the complex interaction of multiple factors. The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy-related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes SCN1A and SCN5A and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage-gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia- and epilepsy-associated VGSC genes.

METHODS: To address this hypothesis, we evaluated whole-exome sequencing data from infants and children with SUDP for variants in VGSC genes, reviewed the literature for all SUDP-associated variants in VGSCs, applied a novel paralog analysis to all variants, and evaluated all variants according to American College of Medical Genetics and Genomics (ACMG) guidelines.

RESULTS: In our cohort of 73 cases of SUDP, we assessed 11 variants as pathogenic in SCN1A, SCN1B, and SCN10A, genes with long-standing disease associations, and in SCN3A, SCN4A, and SCN9A, VGSC gene paralogs with more recent disease associations. From the literature, we identified 82 VGSC variants in SUDP cases. Pathogenic variants clustered at conserved amino acid sites intolerant to variation across the VGSC genes, which is unlikely to occur in the general population (p 

CONCLUSION: We report variants in several VGSC genes in cases with SUDP, involving both arrhythmia- and epilepsy-associated genes. Accurate variant assessment as well as future studies are essential for an improved understanding of the contribution of sodium channel-related variants to SUDP.

DOI10.1002/mgg3.1309
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/32449611?dopt=Abstract

Alternate JournalMol Genet Genomic Med
PubMed ID32449611
Grant List / / Fulbright Association /
/ / Belgian American Educational Foundation /
PDM/17/195 / / KU Leuven /
/ / Citizens United for Research in Epilepsy /
R21HD096355-01 / / Eunice Kennedy Shriver National Institute of Child Health and Human Development /