Evidence-Based Assessment of Congenital Heart Disease Genes to Enable Returning Results in a Genomic Study. (21st February 2023)

• Record Type: Journal Article
• Authors: Griffin, Emily L.; Nees, Shannon N.; Morton, Sarah U.; Wynn, Julia; Patel, Nihir; Jobanputra, Vaidehi; Robinson, Scott; Kochav, Stephanie M.; Tao, Alice; Andrews, Carli; Cross, Nancy; Geva, Judith; Lanzilotta, Kristen; Ritter, Alyssa; Taillie, Eileen; Thompson, Alexandra; Meyer, Chris; Akers, Rachel; King, Eileen C.; Cnota, James F; Kim, Richard W.; Porter, George A.; Brueckner, Martina; Seidman, Christine E.; Shen, Yufeng; Gelb, Bruce D.; Goldmuntz, Elizabeth; Newburger, Jane W.; Roberts, Amy E.; Chung, Wendy K.
• Is Part Of: Circulation. Volume 16:Number 2(2023)
• Page Start: e003791
• Publication Date: 2023-02-21
• Subjects: ClinGen -- congenital heart disease -- gene curation; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Genetics -- Periodicals; Cardiovascular Diseases -- genetics; Precision Medicine; Periodical; Fulltext; Internet Resources; Periodicals; Electronic journals; Periodicals; 616.1042
• DOI: 10.1161/CIRCGEN.122.003791
• Languages: English
• ISSNs: 2574-8300

Abstract

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.