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

Anne M Rochtus,Dennis Lal,Richard D Goldstein,Catherine A Brownstein,Eduardo Pérez-Palma,Robin Haynes,Annapurna H Poduri,Ingrid A Holm

doi:10.1002/mgg3.1309

Abstract

BackgroundSudden 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.MethodsTo 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.ResultsIn 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 < .0001). For 54% of variants previously reported in literature, we identified conflicting evidence regarding pathogenicity when applying ACMG criteria and modern population data.ConclusionWe 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.

Highlights

Sudden Unexpected Death in Pediatrics (SUDP) encompasses a tragic set of conditions, including Sudden Infant Death Syndrome (SIDS) and Sudden Unexplained Death in Childhood (SUDC), affecting children under and over 1 year of age, respectively
Genetics and clinical characteristics of our cases We identified 13 variants that we determined to be pathogenic or likely pathogenic in genes encoding for Voltage-gated sodium channels (VGSCs) in 11 patients, using ACMG criteria [44] (Table 2)
One patient had two variants in SCN1A (p.Leu1296Met, p.Glu1308Asp)[9], one patient had a variant in SCN3A (p.Ala1804Val) and in SCN10A (c.4386+1G>C), and two siblings carried the same variant in SCN1B (p.Trp179Ter)

Summary

Introduction

Sudden Unexpected Death in Pediatrics (SUDP) encompasses a tragic set of conditions, including Sudden Infant Death Syndrome (SIDS) and Sudden Unexplained Death in Childhood (SUDC), affecting children under and over 1 year of age, respectively. These conditions are hypothesized to involve heterogeneous and multifactorial etiologies, conceptualized as a ‘triple-risk’ model with a convergence of intrinsic, developmental, and environmental vulnerabilities contributing to death [1,2]. Variants in SCN1A [40,41], SCN2A [28,42] and SCN8A [29,30,42] have been associated with SUDEP

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