Tseng Zian H, Salazar James W, Wojciak Julianne, Devine W Patrick, Kinkead Brielle A, Yee Matthew, Eik David, Feng Jean, Connolly Andrew J, Moffatt Ellen
Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of California-San Francisco, San Francisco, California, USA; Cardiovascular Genetics Center, University of California-San Francisco, San Francisco, California, USA.
Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of California-San Francisco, San Francisco, California, USA. Electronic address: https://twitter.com/JamesSalazarMD.
JACC Clin Electrophysiol. 2025 Mar;11(3):471-481. doi: 10.1016/j.jacep.2024.10.027. Epub 2024 Dec 18.
Sudden cardiac death (SCD) genetic studies neglect the majority occurring in older decedents with cardiovascular pathology.
This study sought to determine the burden of genetic disease in unselected adult sudden deaths by precision genotype-postmortem phenotype correlation.
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.
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.
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.
心脏性猝死（SCD）的遗传学研究忽略了大多数发生在患有心血管疾病的老年死者中的病例。
本研究旨在通过精确的基因型与尸检表型相关性来确定非选择性成人猝死中遗传疾病的负担。
作者利用尸检、组织学和毒理学来判定死因，并在2011年2月至2018年1月提交给县法医的18至90岁的推定SCD病例中识别出高疑似表型（如肥厚型心肌病）。他们检测了231个与猝死相关的基因，并将基因型与尸检表型相关联，包括心肌分析。获取了高疑似表型病例的家族史。
在856例尸检的推定SCD病例中，359例的家属同意，最终306例（66%由心脏原因导致）接受了基因检测（平均年龄62岁，74%为男性）。75例符合高疑似表型标准（8.8%），其中36例接受了检测；18个家庭与遗传咨询师进行了面谈。我们发现14例具有常染色体显性或X连锁致病/可能致病（P/LP）变异（明显检出率4.6%）；6例病因一致（校正检出率2%）。限于尸检确诊的心脏原因（2.5%）和高疑似表型（2.7%）的检出率相似。14例高疑似死者的心肌基因分型与阴性血液基因分型相符，因此不支持体细胞镶嵌现象。一名无表型的P/LP PKP2携带者的心肌RNA显示无义介导逃避是不完全外显的潜在机制。一半的高疑似病例有相关疾病或猝死的家族史。
在这项为期7年的全县研究中，经基因型与表型一致性校正后，2%的总猝死病例和2.5%的确诊SCD病例有可识别的遗传病因。这些结果不支持对社区猝死病例进行常规基因检测，尤其是在没有尸检的情况下。
