Heritable Burden of Community Sudden Death by Autopsy and Molecular Phenotyping for Precision Genotype Correlation

IF 8 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

JACC. Clinical electrophysiology Pub Date : 2025-03-01 DOI:10.1016/j.jacep.2024.10.027

Zian H. Tseng MD, MAS , James W. Salazar MD, MAS , Julianne Wojciak MS , W. Patrick Devine MD, PhD , Brielle A. Kinkead BS , Matthew Yee BA , David Eik BA , Jean Feng PhD , Andrew J. Connolly MD, PhD , Ellen Moffatt MD

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引用次数: 0

Abstract

Background

Sudden cardiac death (SCD) genetic studies neglect the majority occurring in older decedents with cardiovascular pathology.

Objectives

This study sought to determine the burden of genetic disease in unselected adult sudden deaths by precision genotype–postmortem phenotype correlation.

Methods

The authors used autopsy, histology, and toxicology to adjudicate cause and identify high-suspicion phenotypes (eg, hypertrophic cardiomyopathy) among presumed SCDs aged 18 to 90 years referred to the county medical examiner from February 2011 to January 2018. They tested 231 genes associated with sudden death and correlated genotype with postmortem phenotypes, including myocardial analysis. Family history in high-suspicion phenotype cases was obtained.

Results

Of 856 autopsied presumed SCDs, families of 359 consented and 306 cases (66% cardiac cause) ultimately underwent genetic testing (mean age 62 years, 74% male). Seventy-five cases met high-suspicion phenotype criteria (8.8%), of which 36 underwent testing; 18 families met with a genetic counselor. We found 14 cases with autosomal dominant or X-linked pathogenic/likely pathogenic (P/LP) variants (apparent yield 4.6%); 6 had concordant cause (corrected yield 2%). Yields restricted to autopsy-confirmed cardiac causes (2.5%) and high-suspicion phenotypes (2.7%) were similar. Myocardial genotyping in 14 high-suspicion decedents matched negative blood genotyping, thus did not support somatic mosaicism. Myocardial RNA in a P/LP PKP2 carrier without phenotype demonstrated nonsense-mediated escape as potential mechanism for incomplete penetrance. One-half of high-suspicion cases had a family history of a related condition or sudden death.

Conclusions

In this 7-year countywide study, 2% of total sudden deaths and 2.5% of confirmed SCDs had identifiable genetic cause, corrected for genotype–phenotype concordance. These results do not support routine genetic testing for community sudden deaths, particularly without autopsy.

查看原文本刊更多论文

社区猝死的尸检遗传负担与精确基因型相关性的分子表型分析。

背景：心源性猝死（SCD）遗传学研究忽视了大多数发生在心血管病理的老年死者。目的：本研究试图通过精确的基因型-死后表型相关性来确定非选择性成人猝死的遗传疾病负担。方法：作者在2011年2月至2018年1月向县法医提交的18至90岁的疑似SCDs中，采用尸检、组织学和毒理学方法确定病因并确定高可疑表型（例如肥厚性心肌病）。他们测试了231个与猝死相关的基因，以及与死后表型相关的基因型，包括心肌分析。获得高怀疑表型病例的家族史。结果：在856例尸检推定SCDs中，359例家庭同意，306例（66%为心脏原因）最终接受了基因检测（平均年龄62岁，男性74%）。75例（8.8%）符合高怀疑表型标准，其中36例接受了检测；18个家庭见了基因咨询师。我们发现14例常染色体显性或x连锁致病性/可能致病性（P/LP）变异（表观发生率4.6%）；6例病因一致（校正率2%）。局限于尸检证实的心脏原因（2.5%）和高怀疑表型（2.7%）的产率相似。14例高怀疑死亡患者的心肌基因分型与血液基因分型阴性相匹配，因此不支持体细胞嵌合。无表型的P/LP PKP2携带者的心肌RNA显示无义介导的逃逸是不完全外显的潜在机制。一半的高怀疑病例有相关疾病或猝死家族史。结论：在这项为期7年的全县研究中，2%的总猝死和2.5%的确诊SCDs具有可识别的遗传原因，校正了基因型-表型一致性。这些结果不支持对社区猝死进行常规基因检测，特别是在没有尸检的情况下。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

JACC. Clinical electrophysiology CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

10.30

自引率

5.70%

发文量

250

期刊介绍： JACC: Clinical Electrophysiology is one of a family of specialist journals launched by the renowned Journal of the American College of Cardiology (JACC). It encompasses all aspects of the epidemiology, pathogenesis, diagnosis and treatment of cardiac arrhythmias. Submissions of original research and state-of-the-art reviews from cardiology, cardiovascular surgery, neurology, outcomes research, and related fields are encouraged. Experimental and preclinical work that directly relates to diagnostic or therapeutic interventions are also encouraged. In general, case reports will not be considered for publication.