Research Unit of Internal Medicine, University of Oulu and University Hospital of Oulu, Finland (M.J.J., L.H., K.K., H.V.H.)
Research Unit of Internal Medicine, University of Oulu and University Hospital of Oulu, Finland (M.J.J., L.H., K.K., H.V.H.).
Circulation. 2018 Jun 19;137(25):2716-2726. doi: 10.1161/CIRCULATIONAHA.117.032175.
Myocardial fibrosis is a common postmortem finding among young individuals with sudden cardiac death. Because there is no known single cause, we tested the hypothesis that some cases of myocardial fibrosis in the absence of identifiable causes (primary myocardial fibrosis [PMF]) are associated with genetic variants.
Tissue was obtained at autopsy from 4031 consecutive individuals with sudden cardiac death in Northern Finland, among whom PMF was the only structural finding in 145 subjects with sudden cardiac death. We performed targeted next-generation sequencing using a panel of 174 genes associated with myocardial structure and ion channel function when autopsies did not identify a secondary basis for myocardial fibrosis. All variants with an effect on protein and with a minor allele frequency <0.01 were classified as pathogenic or variants of uncertain significance on the basis of American College of Medical Genetics consensus guidelines.
Among the 96 specimens with DNA passing quality control (66%), postmortem genetic tests identified 24 variants of known or uncertain significance in 26 subjects (27%). Ten were pathogenic/likely pathogenic variants in 10 subjects (10%), and 14 were variants of uncertain significance in 11 genes among 16 subjects (17%). Five variants were in genes associated with arrhythmogenic right ventricular cardiomyopathy, 6 in hypertrophic cardiomyopathy-associated genes, and 11 in dilated cardiomyopathy-associated genes; 2 were not associated with these disorders. Four unique variants of uncertain significance cosegregated among multiple unrelated subjects with PMF. No pathogenic/likely pathogenic variants were detected in ion channel-encoding genes.
A large proportion of subjects with PMF at autopsy had variants in genes associated with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy without autopsy findings of those diseases, suggesting that PMF can be an alternative phenotypic expression of structural disease-associated genetic variants or that risk-associated fibrosis was expressing before the primary disease. These findings have clinical implications for postmortem genetic testing and family risk profiling.
心肌纤维化是年轻人心源性猝死患者常见的死后发现。由于没有已知的单一原因，我们检验了这样一种假设，即某些原因不明的心肌纤维化病例（原发性心肌纤维化[PMF]）与遗传变异有关。
在芬兰北部连续 4031 例心源性猝死患者的尸检中获得组织，其中 145 例心源性猝死患者尸检时仅发现结构性心肌纤维化。当尸检未发现心肌纤维化的继发性病因时，我们使用与心肌结构和离子通道功能相关的 174 个基因的靶向下一代测序对组织进行了检测。根据美国医学遗传学学院的共识指南，所有对蛋白质有影响且次要等位基因频率<0.01 的变异都被归类为致病性或意义未明的变异。
在通过质量控制的 96 个标本中（66%），死后基因检测在 26 名受试者（27%）中确定了 24 种已知或意义未明的变异。10 名受试者（10%）携带 10 种致病性/可能致病性变异，16 名受试者（17%）的 11 种基因中有 14 种意义未明的变异。5 种变异位于致心律失常性右心室心肌病相关基因中，6 种位于肥厚型心肌病相关基因中，11 种位于扩张型心肌病相关基因中；2 种与这些疾病无关。在多个无亲缘关系的 PMF 患者中，发现了 4 种意义未明的独特变异，且具有共分离性。离子通道编码基因中未检测到致病性/可能致病性变异。
尸检中很大一部分 PMF 患者的基因中存在与致心律失常性右心室心肌病、扩张型心肌病和肥厚型心肌病相关的变异，但尸检未发现这些疾病的发现，这表明 PMF 可以是结构性疾病相关遗传变异的替代表型表达，或者风险相关的纤维化在主要疾病之前就已经表达了。这些发现对死后基因检测和家族风险分析具有临床意义。
