期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：52
DOI：10.1073/pnas.2115140118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
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.
关键词：sudden death in children; cardiac arrhythmia; seizure disorder; genetics; calcium signaling
