Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes
Abstract
Congenital heart disease (CHD) is a leading cause of infant mortality. We analyzed de novo mutations (DNMs) and very rare transmitted/unphased damaging variants in 248 prespecified genes in 11,555 CHD probands. The results identified 60 genes with a significant burden of heterozygous damaging variants. Variants in these genes accounted for CHD in 10.1% of probands with similar contributions from de novo and transmitted variants in parent–offspring trios that showed incomplete penetrance. DNMs in these genes accounted for 58% of the signal from DNMs. Thirty-three genes were linked to a single CHD subtype while 12 genes were associated with 2 to 4 subtypes. Seven genes were only associated with isolated CHD, while 37 were associated with 1 or more extracardiac abnormalities. Genes selectively expressed in the cardiomyocyte lineage were associated with isolated CHD, while those widely expressed in the brain were also associated with neurodevelopmental delay (NDD). Missense variants introducing or removing cysteines in epidermal growth factor (EGF)-like domains of NOTCH1 were enriched in tetralogy of Fallot and conotruncal defects, unlike the broader CHD spectrum seen with loss of function variants. Transmitted damaging missense variants in MYH6 were enriched in multiple CHD phenotypes and account for ~1% of all probands. Probands with characteristic mutations causing syndromic CHD were frequently not diagnosed clinically, often due to missing cardinal phenotypes. CHD genes that were positively or negatively associated with development of NDD suggest clinical value of genetic testing. These findings expand the understanding of CHD genetics and support the use of molecular diagnostics in CHD.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (46)
Michael C. Sierant
Department of Genetics, Yale School of Medicine
Sheng Chih Jin
Kaya Bilguvar
Sarah U. Morton
Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital
Weilai Dong
Department of Genetics, Yale School of Medicine
Wei Jiang
Ziyu Lu
Boyang Li
Department of Mechanical Engineering and Materials Science
Francesc Lopez-Giraldez
Irina Tikhonova
Yale Center for Genome Analysis, Yale University
Xue Zeng
Department of Genetics, Yale School of Medicine
Qiongshi Lu
Department of Biostatistics and Medical Informatics, University of Wisconsin
Jungmin Choi
Department of Genetics, Yale School of Medicine
Junhui Zhang
Carol Nelson-Williams
Department of Genetics, Yale School of Medicine
James R. Knight
Yale Center for Genome Analysis, Yale University
Hongyu Zhao
Junyue Cao
Shrikant Mane
Stanley C. Sedore
Department of Pediatrics, Section of Cardiology, Yale School of Medicine
Peter J. Gruber
Department of Surgery, Yale University School of Medicine
Monkol Lek
Department of Genetics, Yale School of Medicine
Elizabeth Goldmuntz
Division of Cardiology, Children’s Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania
John Deanfield
Institute of Cardiovascular Science, University College London
Alessandro Giardini
Pediatric Cardiology, Great Ormond Street Hospital
Seema Mital
Mark Russell
Department of Pediatrics and Communicable Diseases, University of Michigan
J. William Gaynor
Division of Cardiothoracic Surgery, Children's Hospital of Philadelphia
Eileen King
Department of Pediatrics, University of Cincinnati
Michael Wagner
Deepak Srivastava
Yufeng Shen
Department of Systems Biology, Columbia University Irving Medical Center
Daniel Bernstein
Department of Pediatrics, Cardiology, Stanford University
George A. Porter
Department of Pediatrics, Section of Cardiology, Yale School of Medicine
Jane W. Newburger
Department of Cardiology, Boston Children’s Hospital, Harvard Medical School
Jonathan G. Seidman
Amy E. Roberts
Department of Cardiology, Boston Children’s Hospital, Harvard Medical School
Mark Yandell
Department of Human Genetics, University of Utah and School of Medicine
H. Joseph Yost
Department of Human Genetics, University of Utah and School of Medicine
Martin Tristani-Firouzi
Division of Pediatric Cardiology, University of Utah
Richard Kim
Pediatric Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center
Wendy K. Chung
Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School
Bruce D. Gelb
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai
Christine E. Seidman
Martina Brueckner
Department of Genetics, Yale School of Medicine
Richard P. Lifton
Laboratory of Human Genetics and Genomics, The Rockefeller University