Confirmation of Cause of Death Via Comprehensive Autopsy and Whole Exome Molecular Sequencing in People With Epilepsy and Sudden Unexpected Death

Wang

et al. 2022

JAHA

Background Dilated cardiomyopathy (DCM), characterized by progressive left ventricular enlargement and systolic dysfunction, is the most common type of cardiomyopathy and a leading cause of heart failure and cardiac death. Accumulating evidence underscores the critical role of genetic defects in the pathogenesis of DCM, and >250 genes have been implicated in DCM to date. However, DCM is of substantial genetic heterogeneity, and the genetic basis underpinning DCM remains elusive in most cases. Methods and Results By genome‐wide scan with microsatellite markers and genetic linkage analysis in a 4‐generation family inflicted with autosomal‐dominant DCM, a new locus for DCM was mapped on chromosome 15q13.1–q13.3, a 4.77‐cM (≈3.43 Mbp) interval between markers D15S1019 and D15S1010, with the largest 2‐point logarithm of odds score of 5.1175 for the marker D15S165 at recombination fraction (θ)=0.00. Whole‐exome sequencing analyses revealed that within the mapping chromosomal region, only the mutation in the KLF13 gene, c.430G>T (p.E144X), cosegregated with DCM in the family. In addition, sequencing analyses of KLF13 in another cohort of 266 unrelated patients with DCM and their available family members unveiled 2 new mutations, c.580G>T (p.E194X) and c.595T>C (p.C199R), which cosegregated with DCM in 2 families, respectively. The 3 mutations were absent from 418 healthy subjects. Functional assays demonstrated that the 3 mutants had no transactivation on the target genes ACTC1 and MYH7 (2 genes causally linked to DCM), alone or together with GATA4 (another gene contributing to DCM), and a diminished ability to bind the promoters of ACTC1 and MYH7 . Add, the E144X‐mutant KLF13 showed a defect in intracellular distribution. Conclusions This investigation indicates KLF13 as a new gene predisposing to DCM, which adds novel insight to the molecular pathogenesis underlying DCM, implying potential implications for prenatal prevention and precision treatment of DCM in a subset of patients.

Section: Methodsmentioning

confidence: 99%

KLF13 Loss‐of‐Function Mutations Underlying Familial Dilated Cardiomyopathy

Wang

et al. 2022

JAHA

“…DNA sequencing is another potential strategy to identify a child that is at risk to succumb to SUID. DNA sequencing has already identified genes related to cardiac, neurologic, and metabolic disorders that could be linked to SUID (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). The early identification of high-risk genes could potentially also be important for preventing mortality and morbidity for children that survive beyond the one-year window for SUID.…”

Section: Introductionmentioning

confidence: 99%

Known pathogenic gene variants and new candidates detected in Sudden Unexpected Infant Death using Whole Genome Sequencing

Bard,

Clark,

Cosgun

et al. 2023

Preprint

PurposeIn this study we performed WGS of children that succumbed to SUID during their first year of life to gain insights into potential genetic risk factors that could contribute to an infant’s vulnerability to this tragic outcome.MethodsWhole genome sequencing was performed on 145 SUID cases, and 576 healthy adult controls. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences using computational tools.ResultsIn 63.4% of our cohort, we identified 156 variants of interest in 86 genes, including 128 rare/ultra-rare variants in 71 genes that were previously associated with SIDS/SUID/SUDP. Eighty-eight variants were found in 43 genes that can be characterized as cardiac genes, and have previously been associated with cardiomyopathies, Brugada and Long QT syndromes, among others. Twenty-nine variants were also found in 22 genes previously reported in SIDS/SUID/SUDP that are related to neurologic function. Nineteen variants were found in 13 genes that are reported to be pathogenic for various systemic disorders, 11 of which occurred in six genes that have been previously described in SIDS/SUID/SUDP and eight that have not. We also identified 20 variants in eight genes implicated in the response to hypoxia and the regulation of reactive oxygen species (ROS) not previously described in SIDS/SUID/SUDP.ConclusionOur study confirms and further expands the list of genetic variants associated with SUID. The abundance of genes associated with heart disease and the discovery of variants associated with the redox metabolism has important mechanistic implications for the pathophysiology of SUID.

“…Studies using genetic testing have revealed a significant portion (∼12-30%) of children/young adults with sudden cardiac death (SCD) that have pathogenic rare variants in genes associated with arrhythmic syndromes and cardiomyopathy 6, 8 . In addition, rare variants in genes associated with epilepsy have also been associated with SCA in the young 9 .…”

Section: Introductionmentioning

confidence: 99%

Rare Genetic Variants Associated with Sudden Cardiac Arrest in the Young: A Prospective, Population-Based Study

Holmström

Chaudhary

Nakamura

et al. 2022

Preprint

Background: Sudden cardiac arrest (SCA) is a rare and tragic event among the young and often caused by inherited cardiac disease. Previous studies have investigated referral cohorts, but the prevalence of disease-associated variants is unclear at the community level. We investigated the prevalence of genetic variants among community-based cases of SCA aged <21 years. Methods: The study sample is obtained from two prospective, community-based studies of out-of-hospital SCA ongoing in the Portland, OR metro area (population ~1 million) and Ventura County CA (population ~850,000). We performed next-generation whole genome sequencing and then rare variant analysis of candidate genes associated with arrhythmic syndromes and cardiomyopathy in ClinGen. Results: The mean age of the study subjects was 11.3 years (SD 8.0 years, 30% non-white, 45% female). We found that 36 of 52 young SCA victims (69%) harbored uncertain, likely pathogenic (LP), or pathogenic (P) variants. Eight subjects (15%) carried 9 LP/P variants. Patients with clinical histories suggesting primary arrhythmic syndromes or hypertrophic cardiomyopathy were more likely to harbor clinically actionable variants or variants of unknown significance (VUS), than subjects with myocarditis, sudden infant death syndrome, or sudden arrhythmic death. Variants were more likely to be classified as LP/P among Whites (8/9, 88.9%) as compared to non-Whites (1/9, 11.1%, p = 0.036). Conclusions: A notable proportion of young SCA victims in the community harbor rare, potentially disease-associated gene variants, and further studies are needed to understand variants of unknown significance. We identified differences by phenotype groups and race that have potential implications for genetic testing.