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. 2023 Apr;16(2):e003791.
doi: 10.1161/CIRCGEN.122.003791. Epub 2023 Feb 21.

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

Emily L Griffin #  1 , Shannon N Nees #  2 , Sarah U Morton #  3   4 , Julia Wynn  1 , Nihir Patel  5 , Vaidehi Jobanputra  6 , Scott Robinson  1 , Stephanie M Kochav  7   8 , Alice Tao  9 , Carli Andrews  1 , Nancy Cross  10 , Judith Geva  11 , Kristen Lanzilotta  12 , Alyssa Ritter  12   13 , Eileen Taillie  14 , Alexandra Thompson  15 , Chris Meyer, Rachel Akers  16 , Eileen C King  16 , James F Cnota  17 , Richard W Kim  18 , George A Porter Jr  14 , Martina Brueckner  19 , Christine E Seidman  20   21   22 , Yufeng Shen  23 , Bruce D Gelb  24 , Elizabeth Goldmuntz  12 , Jane W Newburger  11   4 , Amy E Roberts  25 , Wendy K Chung  1   8
Affiliations

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

Emily L Griffin et al. Circ Genom Precis Med. 2023 Apr.

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.

Keywords: ClinGen; congenital heart disease; gene curation.

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Figures

Figure 1.
Figure 1.. Candidate Gene Curation Flowchart.
The progression of candidate gene curation is demonstrated in the below flowchart. Genes were initially filtered based on preliminary screening of the relevant literature in order to determine which required full curation. Evidence was quantified according to the ClinGen criteria and led to categorization of definitive, strong, moderate, or limited evidence of CHD association.
Figure 2.
Figure 2.. The Sequence of Returning Results Across the Consortia.
This flowchart demonstrates the sequence of the return of results across the consortia with the corresponding number of probands eligible at each stage. Percentages demonstrate the fraction of probands that proceeded through the process. Participants who were eligible for the impact survey, including parents of probands and adult probands, are included as the final datapoint.
Figure 3.
Figure 3.. Utility of Results for Adult Probands.
Results from surveys taken by probands who were adults at the time of result return regarding their perception of the utility of genetic results.
Figure 4.
Figure 4.. Utility of Results for Parents of Probands.
Results from surveys taken by parents of probands regarding their perception of the utility of genetic results.
See this image and copyright information in PMC

Comment in

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