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

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.

SUBMITTER: Halvorsen M

PROVIDER: S-EPMC8719874 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Halvorsen Matthew M Gould Laura L Wang Xiaohan X Grant Gariel G Moya Raquel R Rabin Rachel R Ackerman Michael J MJ Tester David J DJ Lin Peter T PT Pappas John G JG Maurano Matthew T MT Goldstein David B DB Tsien Richard W RW Devinsky Orrin O

Proceedings of the National Academy of Sciences of the United States of America 20211201 52

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 overtransmiss ...[more]

PMID: 34930847

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Project description:Sudden unexplained death in childhood (SUDC) is death of a child over 1 year of age that is unexplained after review of clinical history, circumstances of death, and complete autopsy with ancillary testing. Multiple etiologies may cause SUDC. SUDC and sudden unexpected death in epilepsy (SUDEP) share clinical and pathological features, suggesting some similarities in mechanism of death and possible abnormalities in hippocampus and cortex. To identify molecular signaling pathways, we performed label-free quantitative mass spectrometry on microdissected frontal cortex, hippocampal dentate gyrus (DG), and cornu ammonis (CA1-3) in SUDC (n = 19) and pediatric control cases (n = 19) with an explained cause of death. At a 5% false discovery rate (FDR), we found differential expression of 660 proteins in frontal cortex, 170 in DG, and 57 in CA1-3. Pathway analysis of altered proteins identified top signaling pathways associated with activated oxidative phosphorylation (p = 6.3 × 10-15, z = 4.08) and inhibited EIF2 signaling (p = 2.0 × 10-21, z = - 2.56) in frontal cortex, and activated acute phase response in DG (p = 8.5 × 10-6, z = 2.65) and CA1-3 (p = 4.7 × 10-6, z = 2.00). Weighted gene correlation network analysis (WGCNA) of clinical history indicated that SUDC-positive post-mortem virology (n = 4/17) had the most significant module in each brain region, with the top most significant associated with decreased mRNA metabolic processes (p = 2.8 × 10-5) in frontal cortex. Additional modules were associated with clinical history, including fever within 24 h of death (top: increased mitochondrial fission in DG, p = 1.8 × 10-3) and febrile seizure history (top: decreased small molecule metabolic processes in frontal cortex, p = 8.8 × 10-5) in all brain regions, neuropathological hippocampal findings in the DG (top: decreased focal adhesion, p = 1.9 × 10-3). Overall, cortical and hippocampal protein changes were present in SUDC cases and some correlated with clinical features. Our studies support that proteomic studies of SUDC cohorts can advance our understanding of the pathogenesis of these tragedies and may inform the development of preventive strategies.

Dataset Information

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

Publications

De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca<sup>2+</sup> regulation.

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