Genetic Determinants of Sudden Unexpected Death in Pediatrics

Genet Med. 2022 Apr;24(4):839-850. doi: 10.1016/j.gim.2021.12.004. Epub 2022 Jan 10.

Abstract

Purpose: This study aimed to evaluate genetic contributions to sudden unexpected death in pediatrics (SUDP).

Methods: 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.

Results: 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).

Conclusion: 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.

Keywords: Intrinsic vulnerability; Sudden infant death syndrome; Sudden unexpected death in pediatrics; Sudden unexpected infant death; Sudden unexplained death in childhood.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Child
  • Child, Preschool
  • DNA-Binding Proteins
  • Death, Sudden*
  • Exome / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Pediatrics*
  • Phenotype
  • Whole Exome Sequencing

Substances

  • Adaptor Proteins, Signal Transducing
  • BRPF1 protein, human
  • DNA-Binding Proteins