Genetic Contribution to End-Stage Cardiomyopathy Requiring Heart Transplantation

作者：Yuri Kim, Oddný Brattberg Gunnarsdóttir, Anissa Viveiros, Daniel Reichart, Daniel Quiat, Jon A. L. Willcox, Hao Zhang, Huachen Chen, Justin J. Curran, Daniel Kim, Simon Urschel, Barbara McDonough, Joshua Gorham, Steven R. DePalma, Jonathan G. Seidman, Christine E. Seidman, Gavin Y. Oudit · 发表于：Circulation Genomic and Precision Medicine · 年份：2023 · DOI：10.1161/circgen.123.004062 · 被引用次数：20 · 研究领域：Cardiomyopathy and Myosin Studies、Viral Infections and Immunology Research、Cardiovascular Effects of Exercise

Background: 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. Methods: 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. Results: 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 ( P =8.30×10 -4 ). The prevalence of causal genetic variants was significantly higher in end-stage than in previously reported ambulatory adult dilated cardiomyopathy cases ( P <0.001). Among remaining samples with unexplained causes, no damaging mitochondrial variants were identified, but 28 samp...