Genetic Determinants of Sudden Unexpected Death in Pediatrics

• DOI: 10.1016/j.gim.2021.12.004
• Publication Date: 2022-01-10T22:27:55Z
• Authors: Hyun Yong Koh; Alireza Haghighi; Christine Keywan; Sanda Alexandrescu; Erin Plews-Ogan; Elisabeth A. Haas; Catherine A. Brow...; Sara O. Vargas; Robin L. Haynes; Gerard T. Berry; Ingrid A. Holm; Annapurna H. Poduri; Richard D. Goldstein
• Keywords: DNA-Binding Proteins; Death, Sudden; Phenotype; Child, Preschool; Exome Sequencing; Infant, Newborn; Humans; Infant; Exome; Child; Pediatrics; Adaptor Proteins, Signal Transducing; 3. Good health

This study aimed to evaluate genetic contributions to sudden unexpected death in pediatrics (SUDP).We phenotyped and performed exome sequencing for 352 SUDP cases. We analyzed variants in 294 "SUDP genes" with mechanisms plausibly related to sudden death. In a subset of 73 cases with parental data (trios), we performed exome-wide analyses and conducted cohort-wide burden analyses.In total, we identified likely contributory variants in 37 of 352 probands (11%). Analysis of SUDP genes identified pathogenic/likely pathogenic variants in 12 of 352 cases (SCN1A, DEPDC5 [2], GABRG2, SCN5A [2], TTN [2], MYBPC3, PLN, TNNI3, and PDHA1) and variants of unknown significance-favor-pathogenic in 17 of 352 cases. Exome-wide analyses of the 73 cases with family data additionally identified 4 de novo pathogenic/likely pathogenic variants (SCN1A [2], ANKRD1, and BRPF1) and 4 de novo variants of unknown significance-favor-pathogenic. Comparing cases with controls, we demonstrated an excess burden of rare damaging SUDP gene variants (odds ratio, 2.94; 95% confidence interval, 2.37-4.21) and of exome-wide de novo variants in the subset of 73 with trio data (odds ratio, 3.13; 95% confidence interval, 1.91-5.16).We provide strong evidence for a role of genetic factors in SUDP, involving both candidate genes and novel genes for SUDP and expanding phenotypes of disease genes not previously associated with sudden death.