Evidence-Based Assessment of Congenital Heart Disease Genes to Enable Returning Results in a Genomic Study

Abstract

BACKGROUND: Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study. METHODS: Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who received results were asked to complete a post-disclosure survey. RESULTS: A total of 99 genes had a strong or definitive clinical validity classification. Diagnostic yields for copy number variants and exome sequencing were 1.8% and 3.8%, respectively. Thirty-one probands completed clinical laboratory improvement amendments-confirmation and received results. Participants who completed postdisclosure surveys reported high personal utility and no decision regret after receiving genetic results. CONCLUSIONS: The application of ClinGen criteria to CHD candidate genes yielded a list that can be used to interpret clinical genetic testing for CHD. Applying this gene list to one of the largest research cohorts of CHD participants provides a lower bound for the yield of genetic testing in CHD.

A validated heart-specific model for splice-disrupting variants in childhood heart disease

“…We first analyzed WGS data to identify pathogenic or likely pathogenic variants in CHD-associated genes ( Table 2 ). These included 99 Tier 1 CHD genes with moderate, strong, or definitive associations with CHD according to Clinical Genome Resource (ClinGen) criteria (17 isolated CHD genes, 82 syndromic CHD genes) 16 , and 626 Tier 2 CHD genes with more limited association with CHD. Tier 2 genes were identified using published literature, existing databases including Online Mendelian Inheritance in Man (OMIM) 17 , ClinGen 18 , and CHDgene 19 , their inclusion in clinical gene panels, and expert curation.…”

“…Tier 1 CHD genes were selected based on a moderate, strong, or definitive association with CHD according to ClinGen criteria 16 . We further annotated and categorized additional CHD genes using (1) published literature; (2) existing databases including Online Mendelian Inheritance in Man (OMIM) 17 , Clinical Genome Resource (ClinGen) 18 , and CHDgene 19 ; (3) inclusion in clinical gene panels; and (4) expert curation and classified genes with a limited evidence for association with CHD as Tier 2 genes.…”

Genetic Testing in Patients With Congenital Heart Disease: You Do No Harm When Using the Right Tools!

“…In this study, Griffin et al 7 first carefully curated a large (>500) set of genes linked to CHD and subsequently screened a set of 99 curated genes with strong/ definitive gene-disease association in a group of 6767 probands included in the Paediatric Cardiac Genomics Consortium with available genomic data.…”

Noncanonical Splice-Altering Variants: Hidden Culprits of Congenital Heart Disease

“…At present, clinical investigations and genetic testing are largely reserved for patients with familial forms of disease and those with seemingly syndromic disease (ie, those with extracardiac anomalies) and are often limited to established genes and gene sets known to be associated with human disease. 5,6 Additional investigations into CHD etiology, such as gene discovery, analyses beyond known or established genes and noncoding regions of the genome, are usually performed within a research environment. That is not to say, that in time, with improvements in computational and functional analyses as demonstrated by the authors through their evaluation of in silico tool, SpliceAI, advanced computational and functional analyses would not be incorporated into clinical workflows and provide important answers for patients with unexplained disease.…”

“…2,4 Currently, we know of ~100 to 140 genes associated with human disease. 5,6 In patients with syndromic forms of disease (ie, those with CHD and one or more extracardiac anomalies), a significant increase in de novo variants, often in chromatin-modifying genes, has been observed. 2,4 Conversely, in those with nonsyndromic, isolated CHD, inherited rare damaging variants are significantly increased, and mostly reside in established CHD genes including cilia genes.…”