Congenital Heart Disease Expert Curation Panel

ClinGen CHD ECP Project Summary Abstract Congenital heart defects (CHD), defined as structural malformations of the heart and great vessels that are present at birth, are the commonest birth defects, affecting 2-3% of newborns when bicuspid aortic valve is included. While understood to be potentially a heritable trait as early as the mid-1800s, definitive epidemiological evidence supporting the notion that CHD was primarily genetic in its origins has only emerged in the last 35 years. To date, 253 genes contributing to CHD have been established but a far smaller number of genes have been designated as CHD-causing using formal ClinGen gene curation. Furthermore, and there are clinically relevant discrepancies for individual variants (i.e., pathogenic/likely pathogenic vs. benign/likely benign) in a substantial number of these genes. Sequencing-based clinical genetic testing using CHD gene panels facilitates diagnoses for which there are actionable co-morbidities that would often go otherwise undetected, particularly in young infants in whom syndromic features may not yet be evident but available commercial CHD genetic testing panels vary substantially in their gene content. The proposed CHD ECP will bring together experts in CHD genes from around the world which, in a well-organized, ClinGen-compliant manner, will curate gene-CHD pairs and classify their variants. The MPI's and many of the Expert Curation Panel members have extensive prior collaboration on a long-standing NIH-supported consortium (Pediatric Cardiac Genomic Consortium) that has and continues to elucidate the genetic architecture of the trait of interest (CHD) thus bringing significant gene and variant curation experience. An emphasis will be placed on developing experimental evidence criteria for a given CHD trait, drawing from a notably broad range of science (biochemical, cell-based, and animal models of heart development). This effort is well timed as the numbers of potential genes available for clinical genetic testing is rising rapidly and the clinical utility of such testing is well established. Further, candidate CHD genes with compelling human genetic evidence for pathogenicity but scant functional data can be shared with the cardiac developmental research community for consideration. The CHD ECP will fill an important gap in clinical care.