Pediatric cardiomyopathy and the PCM Genes study: A summary with insights on genetic testing, variant interpretation, race and ethnicity

Abstract

BackgroundThe Pediatric Cardiomyopathy Genes study was developed to identify the genetic contributors to pediatric cardiomyopathy and identify genotype-phenotype correlations. Performed by 14 sites in North America as part of research by the Pediatric Cardiomyopathy Registry, the study completed exome sequencing on 528 children with primary dilated, hypertrophic, restrictive, or mixed cardiomyopathies, including left ventricular noncompaction. Aim of reviewThe goal of this review is to summarize recent findings of the PCM Genes studies on clinical genetic testing practices and the genetic architecture of pediatric cardiomyopathy. Identified barriers to clinical implementation of genetic evaluation and testing are examined. The contribution of race, ethnicity and ancestry to cardiomyopathy phenotype, onset, and outcome in the pediatric population is reviewed. Key scientific concepts of reviewEvaluation of clinical genetic testing practices of sites participating in the PCM Genes study identified that increased standardization and comprehensiveness in approach would increase genetic diagnoses by at least 20%. Multiple barriers to genetic testing and evaluation exist and these should be further evaluated in conjunction with reducing practice variation. The concept of bioinformatic interpretation of genetic variation and its role in classification of pathogenesis and disease-association is reviewed. In addition to the expected differences in the yield of genetic testing by cardiomyopathy phenotype or family history, the PCM Genes study identified differences based on ancestry. Improving our understanding of how race and ethnicity correlate with the likelihood of obtaining positive genetic testing results in established genes and identifying ancestry-specific genetic causes are research priorities.