Lessons learned from testing cardiac channelopathy and cardiomyopathy genes in individuals who died suddenly: A two‐year prospective study in a large medical examiner’s office with an in‐house molecular genetics laboratory and genetic counseling services

Williams, Nori; Manderski, Elizabeth; Stewart, Sarah; Bao, Rong; Tang, Yingying

doi:10.1002/jgc4.1157

Cited by 13 publications

(6 citation statements)

References 17 publications

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“…To further prove the role of the reported VUS, computational models of protein structure and functioning are needed, collecting samples from relatives might be recommended (Bittar et al, 2019; Williams et al, 2020). The reported variants should also be investigated in different population databases, disease databases, and the results of the nucleotide change should be analyzed with the help of in silico (computer based) predictive models (Federici & Soddu, 2020).…”

Section: Discussionmentioning

confidence: 99%

Variants of uncertain significance in the era of next-generation sequencing

Levkova

Stoyanova

Benkova-Petrova

et al. 2022

J Am Assoc Nurse Pract

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Next-generation sequencing (NGS) is now widely used in diagnosing rare diseases. However, it has some limitations, such as variants of uncertain significance (VUS). This can present difficulties even for nurse practitioners involved in clinical genetics. We present three cases from our clinical practice: two targeted panel testing and one exome sequencing. Whole blood samples were collected and sent for NGS analysis. In case 1, a VUS was found in the LITAF gene, which is associated with autosomal dominant Charcot–Marie–Tooth disease type 1C. In case 2, a VUS was reported in the MEFV gene, which is associated with autosomal recessive and autosomal dominant familial Mediterranean fever. In these cases, the reported VUS corresponded to the clinical diagnosis. In case 3, two variants in the heterozygous state were found in the ATP7B gene, which is associated with Wilson disease, and the disorder was later clinically recognized. According to the published guidelines, VUSs should not be discussed as a cause for an observed genetic condition. Nevertheless, if the reported variant is in a gene associated with the clinically diagnosed disorder, and there is a strong genotype-phenotype correlation, it could be suggestive of the etiological role of this variant.

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Section: Discussionmentioning

confidence: 99%

Variants of uncertain significance in the era of next-generation sequencing

Levkova

Stoyanova

Benkova-Petrova

et al. 2022

J Am Assoc Nurse Pract

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“…A crucial point in order to perform a genetic analysis is obtaining sample in proper conditions. Currently, up to 40% of samples are not collected adequately for post-mortem genetic study (102). In large part of cases, it impedes a proper diagnosis and results may not be conclusive due to technical impediments and any postmortem changes to the quality of the sample collected during autopsy could have an impact on results (102).…”

Section: Samplesmentioning

confidence: 99%

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death

et al. 2023

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In the forensic medicine field, molecular autopsy is the post-mortem genetic analysis performed to attempt to unravel the cause of decease in cases remaining unexplained after a comprehensive forensic autopsy. This negative autopsy, classified as negative or non-conclusive, usually occurs in young population. In these cases, in which the cause of death is unascertained after a thorough autopsy, an underlying inherited arrhythmogenic syndrome is the main suspected cause of death. Next-generation sequencing allows a rapid and cost-effectives genetic analysis, identifying a rare variant classified as potentially pathogenic in up to 25% of sudden death cases in young population. The first symptom of an inherited arrhythmogenic disease may be a malignant arrhythmia, and even sudden death. Early identification of a pathogenic genetic alteration associated with an inherited arrhythmogenic syndrome may help to adopt preventive personalized measures to reduce risk of malignant arrhythmias and sudden death in the victim’s relatives, at risk despite being asymptomatic. The current main challenge is a proper genetic interpretation of variants identified and useful clinical translation. The implications of this personalized translational medicine are multifaceted, requiring the dedication of a specialized team, including forensic scientists, pathologists, cardiologists, pediatric cardiologists, and geneticists.

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“…Although AA/Black subjects were reported to be more susceptible to SCD than White subjects 3 , 17 and SCD was less prevalent in Asian countries, 5 , 35 , 36 , 37 Kong’s meta‐analysis noted that genetics alone without considering environmental and socioeconomic factors cannot account for disparities in health outcomes between racial or ethnic groups. In a more recent comprehensive review of 254 decedents from SCD, 38 , 39 most of whom were AA/Black subjects (40% AA/Black, 30% Hispanic, 22% White, 5% Asian/Pacific Islander, and 3% mixed/unspecified subjects), a multigene panel composed of 95 genes (Figure 4 ) associated with cardiac channelopathy and cardiomyopathy were investigated using next‐generation sequencing. Twenty‐seven pathogenic/likely pathogenic (P/LP) variants and 99 variants of uncertain significance (VUS) were identified in 11% and 39% of decedents, respectively.…”

Section: Molecular Genetics Of Sudden Unexpected Deathmentioning

confidence: 99%

Racial Disparities in Ion Channelopathies and Inherited Cardiovascular Diseases Associated With Sudden Cardiac Death

Chahine

Fontaine

Boutjdir

2022

JAHA

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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. We discuss factors related to reports in the United States, that the overall mortality attributed to CVD and the number of out‐of‐hospital cardiac arrests are higher among African American/Black subjects when compared with other racial or ethnic groups. African American/Black subjects are disproportionally affected by CVD, including cardiac arrhythmias and sudden cardiac death, thus highlighting a major concern in this population that remains underrepresented in clinical trials with limited genetic testing and device underuse. The proposed solutions include (1) early identification of genetic variants, which is crucial in tailoring a preventive management strategy; (2) inclusion of diverse racial or ethnic groups in clinical trials; (3) compliance with guideline‐directed medical treatment and referral to cardiovascular subspecialists; and (4) training and mentoring of underrepresented junior faculty in cardiovascular health disparities research.

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Lessons learned from testing cardiac channelopathy and cardiomyopathy genes in individuals who died suddenly: A two‐year prospective study in a large medical examiner’s office with an in‐house molecular genetics laboratory and genetic counseling services

Cited by 13 publications

References 17 publications

Variants of uncertain significance in the era of next-generation sequencing

Variants of uncertain significance in the era of next-generation sequencing

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death

Racial Disparities in Ion Channelopathies and Inherited Cardiovascular Diseases Associated With Sudden Cardiac Death

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