Genetic Determinants of Sudden Unexpected Death in Pediatrics

Background: Sudden unexpected death in pediatrics (SUDP) encompasses infant and child deaths without established cause. The objective of this study was to elucidate genetic factors contributing to SUDP, approaching SUDP as an undiagnosed disease with heterogeneous etiologies. Methods: We phenotyped SUDP probands and analyzed exome data for variants in genes plausibly related to sudden death through neurological, cardiac, and systemic/syndromic disease mechanisms, curated into an SUDP gene list. We conducted exome-wide trio analyses when parental data were available and burden analyses comparing cases vs. controls. Findings: Our cohort included 352 probands, 73 with trio data. Age of death ranged from 1 day to 11 years (average 6 months). Analyzing for variants in genes on the SUDP gene list, we identified pathogenic/likely pathogenic (P/LP) variants in 12/352 cases (SCN1A, DEPDC5 [2], GABRG2, SCN5A [2], TTN [2], MYBPC3, PLN, TNNI3, and PDHA1) and variants of uncertain significance-favor pathogenic (VUS-FP) in 17/352. Exome-wide analysis of trios and one family with siblings who died of SUDP identified 4 de novo P/LP variants (SCN1A [2], ANRKD1, and BRPF1), and 5 de novo or X-linked maternally inherited VUS-FP. Overall, we identified likely contributory variants in 38/352 probands (11%). Cohort-wide burden analyses demonstrated an excess of rare damaging variants in genes on the SUDP gene list (OR 2·94; 95% CI, 2·37-4·21) and de novo variants exome-wide (OR 3·31; 95% CI, 2·07-5·30).Interpretation We provide strong evidence for a role of genetic factors in SUDP, implicating neurological and cardiac mechanisms and expanding the phenotypes of disease genes not previously associated with sudden death. Funding: Robert's Program on Sudden Unexpected Death in Pediatrics, Citizens United for Research in Epilepsy through the Isaiah Stone Award, the Cooper Trewin Memorial SUDC Research Fund, Three Butterflies SIDS Foundation, The Florida SIDS Alliance, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development and The National Heart, Lung, and Blood Institute. Declaration of Interest: None to declare. Ethical Approval: Research was conducted with approval from the BCH Institutional Review Board.