Genetic Determinants of Sudden Unexpected Death in Pediatrics.
Koh Hyun Yong et al. Genetics in medicine : official journal of the American College of Medical Genetics 2022 1 (4) 839-850
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 , GABRG2, SCN5A , TTN , 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. 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.
Racial Disparities in Ion Channelopathies and Inherited Cardiovascular Diseases Associated With Sudden Cardiac Death
M Chahine et al, May 2022
Cardiovascular disease (CVD) continues to be the most common cause of death worldwide, and cardiac arrhythmias account for approximately one half of these deaths. The morbidity and mortality from CVD have been reduced significantly over the past few decades; however, disparities in racial or ethnic populations still exist. This review is based on available literature to date and focuses on known cardiac channelopathies and other inherited disorders associated with sudden cardiac death in African American/Black subjects and the role of epigenetics in phenotypic manifestations of CVD, and illustrates existing disparities in treatment and outcomes. The review also highlights the knowledge gaps that limit understanding of the manifestation of phenotypic abnormalities across racial or ethnic groups and discusses disparities associated with device underuse in the management of patients at risk for sudden cardiac death.
Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility
J Barc et al, Nature Genetics, February 24, 2022
Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population.
De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca regulation.
Halvorsen Matthew et al. Proceedings of the National Academy of Sciences of the United States of America 2021 12 (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).