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The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy\u2010related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes\n                      <jats:italic>SCN1A<\/jats:italic>\n                      and\n                      <jats:italic>SCN5A<\/jats:italic>\n                      and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage\u2010gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia\u2010 and epilepsy\u2010associated VGSC genes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To address this hypothesis, we evaluated whole\u2010exome sequencing data from infants and children with SUDP for variants in VGSC genes, reviewed the literature for all SUDP\u2010associated 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In our cohort of 73 cases of SUDP, we assessed 11 variants as pathogenic in\n                      <jats:italic>SCN1A, SCN1B,<\/jats:italic>\n                      and\n                      <jats:italic>SCN10A<\/jats:italic>\n                      , genes with long\u2010standing disease associations, and in\n                      <jats:italic>SCN3A, SCN4A,<\/jats:italic>\n                      and\n                      <jats:italic>SCN9A<\/jats:italic>\n                      , 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\n                      <jats:italic>across<\/jats:italic>\n                      the VGSC genes, which is unlikely to occur in the general population (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a0.0001). For 54% of variants previously reported in literature, we identified conflicting evidence regarding pathogenicity when applying ACMG criteria and modern population data.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We report variants in several VGSC genes in cases with SUDP, involving both arrhythmia\u2010 and epilepsy\u2010associated genes. Accurate variant assessment as well as future studies are essential for an improved understanding of the contribution of sodium channel\u2010related variants to SUDP.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mgg3.1309","type":"journal-article","created":{"date-parts":[[2020,5,25]],"date-time":"2020-05-25T06:35:31Z","timestamp":1590388531000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["The role of sodium channels in sudden unexpected death in pediatrics"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3266-9126","authenticated-orcid":false,"given":"Anne M.","family":"Rochtus","sequence":"first","affiliation":[{"name":"Department of Neurology Boston Children's Hospital and Harvard Medical School Boston MA USA"},{"name":"Robert\u2019s Program on Sudden Death in Pediatrics Boston Children\u2019s Hospital Boston MA USA"},{"name":"Department of Pediatrics University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard D.","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Robert\u2019s Program on Sudden Death in Pediatrics Boston Children\u2019s Hospital Boston MA USA"},{"name":"Department of Pediatrics Boston Children\u2019s Hospital and Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid A.","family":"Holm","sequence":"additional","affiliation":[{"name":"Robert\u2019s Program on Sudden Death in Pediatrics Boston Children\u2019s Hospital Boston MA USA"},{"name":"Department of Pediatrics Boston Children\u2019s Hospital and Harvard Medical School Boston MA USA"},{"name":"Department of Medicine Division of Genetics and Genomics and the Manton Center for Orphan Disease Research Boston Children's Hospital Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine A.","family":"Brownstein","sequence":"additional","affiliation":[{"name":"Robert\u2019s Program on Sudden Death in Pediatrics Boston Children\u2019s Hospital Boston MA USA"},{"name":"Department of Pediatrics Boston Children\u2019s Hospital and Harvard Medical School Boston MA USA"},{"name":"Department of Medicine Division of Genetics and Genomics and the Manton Center for Orphan Disease Research Boston Children's Hospital Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"P\u00e9rez\u2010Palma","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute Lerner Research Institute Cleveland Clinic Cleveland OH USA"},{"name":"Cologne Center for Genomics University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Haynes","sequence":"additional","affiliation":[{"name":"Robert\u2019s Program on Sudden Death in Pediatrics Boston Children\u2019s Hospital Boston MA 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