Division of Cardiovascular Medicine, Brigham and Women's Hospital (Y.K., B.M., C.E.S.).
Department of Genetics, Harvard Medical School, Boston, MA (Y.K., O.B.G., D.R., D.Q., J.A.L.W., J.J.C., J.G., S.R.D., J.G.S., C.E.S.).
Circ Genom Precis Med. 2023 Oct;16(5):452-461. doi: 10.1161/CIRCGEN.123.004062. Epub 2023 Sep 28.
Many cardiovascular disorders propel the development of advanced heart failure that necessitates cardiac transplantation. When treatable causes are excluded, studies to define causes are often abandoned, resulting in a diagnosis of end-stage idiopathic cardiomyopathy. We studied whether DNA sequence analyses could identify unrecognized causes of end-stage nonischemic cardiomyopathy requiring heart transplantation and whether the prevalence of genetic causes differed from ambulatory cardiomyopathy cases.
We performed whole exome and genome sequencing of 122 explanted hearts from 101 adult and 21 pediatric patients with idiopathic cardiomyopathy from a single center. Data were analyzed for pathogenic/likely pathogenic variants in nuclear and mitochondrial genomes and assessed for nonhuman microbial sequences. The frequency of damaging genetic variants was compared among cardiomyopathy cohorts with different clinical severity.
Fifty-four samples (44.3%) had pathogenic/likely pathogenic cardiomyopathy gene variants. The frequency of pathogenic variants was similar in pediatric (42.9%) and adult (43.6%) samples, but the distribution of mutated genes differed (=8.30×10). The prevalence of causal genetic variants was significantly higher in end-stage than in previously reported ambulatory adult dilated cardiomyopathy cases (<0.001). Among remaining samples with unexplained causes, no damaging mitochondrial variants were identified, but 28 samples contained parvovirus genome sequences, including 2 samples with 6- to 9-fold higher levels than the overall mean levels in other samples.
Pathogenic variants and viral myocarditis were identified in 45.9% of patients with unexplained end-stage cardiomyopathy. Damaging gene variants are significantly more frequent among transplant compared with patients with ambulatory cardiomyopathy. Genetic analyses can help define cause of end-stage cardiomyopathy to guide management and risk stratification of patients and family members.
许多心血管疾病会导致晚期心力衰竭，需要进行心脏移植。当排除可治疗的病因后，通常会停止研究以明确病因，最终诊断为终末期特发性扩张型心肌病。我们研究了全外显子组和全基因组测序是否可以识别需要心脏移植的终末期非缺血性心肌病的未被识别病因，以及遗传病因的患病率是否不同于门诊心肌病病例。
我们对来自单一中心的 101 例成年患者和 21 例儿童患者的 122 例心脏进行了全外显子组和全基因组测序，这些患者患有特发性心肌病。对核基因组和线粒体基因组中的致病性/可能致病性变体进行了数据分析，并评估了非人类微生物序列。比较了不同临床严重程度的心肌病队列中破坏性遗传变异的频率。
54 例（44.3%）存在致病性/可能致病性心肌病基因变异。儿科（42.9%）和成年（43.6%）样本的致病性变异频率相似，但突变基因的分布不同（=8.30×10）。与先前报道的门诊成人扩张型心肌病病例相比，终末期病例中因果遗传变异的发生率明显更高（<0.001）。在其他原因不明的样本中，未发现致病性线粒体变异，但 28 例样本含有细小病毒基因组序列，其中 2 例样本的水平比其他样本的总体平均值高 6-9 倍。
在原因不明的终末期心肌病患者中，有 45.9%发现了致病性变异和病毒性心肌炎。与门诊心肌病患者相比，移植患者中破坏性基因变异的频率明显更高。基因分析有助于明确终末期心肌病的病因，从而指导患者和家属的管理和风险分层。
