Cardiovascular Clinical Academic Group and Cardiology Research Section, St George's, University of London, St George's University Hospitals NHS Foundation Trust, Cranmer Terrace, London SW17 0RE, UK.
Department of Medicine, Surgery and Health, University of Trieste, Trieste, Italy.
Europace. 2024 Feb 1;26(2). doi: 10.1093/europace/euae029.
Sudden cardiac death (SCD) may occur in apparently healthy individuals, including athletes. The aim was to investigate the diagnostic role of post-mortem genetic testing, molecular autopsy (MA), in elucidating the cause of SCD in athletes.
We reviewed a database of 6860 consecutive cases of SCD referred to our specialist cardiac pathology centre. All cases underwent detailed cardiac autopsy, and 748 were deemed to be athletes. Of these, 42 (6%) were investigated with MA (28 using a targeted sequencing, 14 exome sequencing). Variants were classified as pathogenic, likely pathogenic, or variant of unknown significance using international guidelines. Clinical information was obtained from referring coroners who completed a detailed health questionnaire. Out of the 42 decedents (average age 35 years old, 98% males) who were investigated with MA, the autopsy was in keeping with a structurally normal heart [sudden arrhythmic death syndrome (SADS)] in n = 33 (78%) cases, followed by arrhythmogenic cardiomyopathy (ACM) in eight (19%) individuals and idiopathic left ventricular fibrosis in one (2%). Death occurred during exercise and at rest in 26 (62%) and 16 (38%) individuals, respectively. Variants that were adjudicated clinically actionable were present in seven cases (17%). There was concordance between the genetic and phenotypic findings in two cases of ACM (in FLNC and TMEM43 genes). None of the variants identified in SADS cases were previously linked to channelopathies. Clinically actionable variants in cardiomyopathy-associated genes were found in five cases of SADS.
The yield of MA in athletes who died suddenly is 17%. In SADS cases, clinically actionable variants were found in cardiomyopathy-associated genes and not in channelopathy-associated genes. Arrhythmogenic cardiomyopathy is a common cause of SCD in athletes, and one in four decedents with this condition had a clinically actionable variant in FLNC and TMEM43 genes.
心源性猝死（SCD）可发生于看似健康的个体，包括运动员。本研究旨在探讨尸检基因检测、分子尸检（MA）在明确运动员 SCD 病因中的诊断作用。
我们回顾了我院 6860 例连续 SCD 病例数据库，所有病例均行详细心脏尸检，748 例被认为是运动员。其中 42 例（6%）进行了 MA 检查（28 例行靶向测序，14 例行外显子组测序）。根据国际指南，将变异分为致病性、可能致病性或意义不明的变异。临床信息由参与尸检的法医通过详细的健康问卷获取。在 42 例接受 MA 检查的死者（平均年龄 35 岁，98%为男性）中，33 例（78%）尸检结果与结构正常心脏一致（突发心律失常性死亡综合征[SADS]），8 例（19%）为心律失常性心肌病（ACM），1 例（2%）为特发性左心室纤维化。26 例（62%）和 16 例（38%）死者的死亡分别发生在运动中和休息时。7 例（17%）存在临床可处理的变异。2 例 ACM（FLNC 和 TMEM43 基因）的遗传和表型发现具有一致性。在 SADS 病例中未发现与通道病相关的变异与先前相关。在 5 例 SADS 病例中发现了与心肌病相关基因的临床可处理变异。
在猝死的运动员中，MA 的检出率为 17%。在 SADS 病例中，在与心肌病相关的基因中发现了临床可处理的变异，而在与通道病相关的基因中未发现。心律失常性心肌病是运动员 SCD 的常见原因，四分之一的此类患者在 FLNC 和 TMEM43 基因中存在临床可处理的变异。
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