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

Authors
  • Griffin, Emily L1
  • Nees, Shannon N2
  • Morton, Sarah U3, 4
  • Wynn, Julia1
  • Patel, Nihir5
  • Jobanputra, Vaidehi6
  • Robinson, Scott1
  • Kochav, Stephanie M7, 8
  • Tao, Alice9
  • Andrews, Carli1
  • Cross, Nancy10
  • Geva, Judith11
  • Lanzilotta, Kristen12
  • Ritter, Alyssa12, 13
  • Taillie, Eileen14
  • Thompson, Alexandra15
  • Meyer, Chris
  • Akers, Rachel16
  • King, Eileen C16
  • Cnota, James F17
  • And 10 more
  • 1 Department of Pediatrics (E.L.G., J.W., S.R., C.A., W.K.C.), Columbia University Irving Medical Center, New York, NY.
  • 2 Nemours Cardiac Center, Nemours Children's Hospital, Wilmington, DE (S.N.N).
  • 3 Division of Newborn Medicine, Department of Medicine (S.U.M.), Boston Children's Hospital, Boston, MA.
  • 4 Department of Pediatrics (S.U.M., J.W.N.), Harvard Medical School, Boston, MA.
  • 5 Mindich Child Health & Development Institute (N.P., B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY.
  • 6 Department of Pathology and Cell Biology (V.J.), Columbia University Irving Medical Center, New York, NY.
  • 7 Division of Cardiology (S.M.K), Columbia University Irving Medical Center, New York, NY.
  • 8 Department of Medicine (S.M.K., W.K.C.), Columbia University Irving Medical Center, New York, NY.
  • 9 Division of Cardiothoracic Surgery (A.T), Children's Hospital of Los Angeles, Los Angeles, CA.
  • 10 Division of Pediatric Cardiology (N.C.), Yale School of Medicine, New Haven, CT.
  • 11 Department of Cardiology (J.G., J.W.N.), Boston Children's Hospital, Boston, MA.
  • 12 Division of Cardiology, Department of Pediatrics (K.L, A.R., E.G.), The Children's Hospital of Philadelphia, Philadelphia, PA.
  • 13 Division of Human Genetics (A.R.), The Children's Hospital of Philadelphia, Philadelphia, PA.
  • 14 Department of Pediatrics, Golisano Children's Hospital, University of Rochester Medical Center, Rochester, NY (E.T. and G.A.P).
  • 15 Vagelos College of Physicians and Surgeons (A.T.), Columbia University Irving Medical Center, New York, NY.
  • 16 Division of Biostatistics & Epidemiology (R.A., E.C.K.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
  • 17 The Heart Institute (J.F.C.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
  • 18 Pediatric Cardiac Surgery (R.W.K), Children's Hospital of Los Angeles, Los Angeles, CA.
  • 19 Department of Genetics and Pediatrics (M.B.), Yale School of Medicine, New Haven, CT.
  • 20 Department of Genetics (C.E.S), Harvard Medical School, Boston, MA.
  • 21 Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (C.E.S.).
  • 22 Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.).
  • 23 Departments of Systems Biology & Biomedical Informatics, Columbia University, New York, NY (Y.S.).
  • 24 Departments of Pediatrics and Genetics & Genomic Sciences (B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY.
  • 25 Division of Genetics, Department of Pediatrics (A.E.R.), Boston Children's Hospital, Boston, MA.
Type
Published Article
Journal
Circulation. Genomic and precision medicine
Publication Date
Apr 01, 2023
Volume
16
Issue
2
Identifiers
DOI: 10.1161/CIRCGEN.122.003791
PMID: 36803080
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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. 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.

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