De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca2+regulation

Matthew Halvorsen, Laura Gould, Xiaohan Wang, Gariel Grant, Raquel Moya, Rachel Rabin, Michael J. Ackerman, David J. Tester, Peter T. Lin, John G. Pappas, Matthew T. Maurano, David B. Goldstein, Richard W. Tsien, Orrin Devinsky

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 "trios" (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10-4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C. Both RYR2 mutations are pathogenic (P = 1.7 × 10-7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10-7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.

Original languageEnglish
Article numbere2115140118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number52
DOIs
StatePublished - 28 Dec 2021
Externally publishedYes

Keywords

  • Calcium signaling
  • Cardiac arrhythmia
  • Genetics
  • Seizure disorder
  • Sudden death in children

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