Abstract
Introduction: Hypertrophic cardiomyopathy (HCM) is a routine indication for genetic testing. However, our understanding of the impact of genetic testing on clinical outcomes is limited. This study systematically summarizes the diagnostic validity of genetic testing for patients with HCM and at-risk relatives. Methods: PubMed (MEDLINE), Embase, CINAHL, and Cochrane Central Library were queried using keywords pertaining to HCM, genetic counseling, and genetic testing. The initial search was conducted on July 7, 2017 and updated on March 2, 2020. Abstracts and full-texts were reviewed for original research studies where genetic testing was performed in ≥10 patients with HCM, or their relatives. A total of 132 articles met inclusion criteria. Review was performed according to PRISMA guidelines. Relevant data were extracted and validated by a second reviewer. Risk of bias and quality were assessed using the Cochrane Risk of Bias or Newcastle-Ottawa tools in duplicate. Disagreements were resolved through discussion or a third reviewer. Pooled analyses were performed using random-effects models. Results: Detection rate was significantly higher in pediatric cohorts compared with adults (56% vs. 42%; p=0.01) and in adults with a family history compared to sporadic cases (59% vs. 33%; p=0.005). Use of current variant interpretation standards from the American College of Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP) significantly lowered adult detection rate from 42% to 33% (p=0.0001). The mean difference in age-of-onset in adults was significantly younger for genotype-positive versus genotype-negative cohorts (8.3 years; p<0.0001), MYH7 versus MYBPC3 (8.2 years; p<0.0001), and individuals with multiple versus single variants (7.0 years; p<0.0002). Disease penetrance in adult cohorts was 62%, but differed significantly depending on if probands were included or excluded (73% vs. 55%; p=0.003). Conclusions: This meta-analysis is the largest, if not the first, to refine and quantify historical understandings of detection rate, genotype-phenotype associations, and disease penetrance for HCM, therefore allowing everyday clinical questions to be answered with more confidence
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