Open AccessDe novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca 2+ regulation
Author(s) -
Matthew Halvorsen,
Laura Gould,
Xiaohan Wang,
Gilbert J. Grant,
Raquel Moya,
Rachel Rabin,
Michael J. Ackerman,
David J. Tester,
Peter T. Lin,
John Pappas,
Matthew T. Maurano,
David B. Goldstein,
Richard W. Tsien,
Orrin Devinsky
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2115140118
Subject(s) - missense mutation , proband , genetics , biology , nonsynonymous substitution , sudden death , mutation , exome sequencing , gene , medicine , genome
Significance Approximately 400 United States children 1 y of age and older die suddenly from unexplained causes annually. We studied whole-exome sequence data from 124 “trios” (decedent child and living parents) to identify genetic risk factors. Nonsynonymous mutations, mostly de novo (present in child but absent in both biological parents), were highly enriched in genes associated with cardiac and seizure disorders relative to controls, and contributed to 9% of deaths. We found significant overtransmission of loss-of-function or pathogenic missense variants in cardiac and seizure disorder genes. Most pathogenic variants were de novo in origin, highlighting the importance of trio studies. Many of these pathogenic de novo mutations altered a protein network regulating calcium-related excitability at submembrane junctions in cardiomyocytes and neurons.