Recessive genetic contribution to congenital heart disease in 5,424 probands
Abstract
Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and candidate gene-based analysis; the recessive contribution to the broad range of CHD phenotypes has been limited. We analyzed whole exome sequences of 5,424 CHD probands. Rare damaging RGs were estimated to contribute to at least 2.2% of CHD, with greater enrichment among laterality phenotypes (5.4%) versus other subsets (1.4%). Among 108 curated human recessive CHD genes, there were 66 RGs, with 54 in 11 genes with >1 RG, 12 genes with 1 RG, and 85 genes with zero. RGs were more prevalent among offspring of consanguineous union (4.7%, 32/675) than among nonconsanguineous probands (0.7%, 34/4749). Founder variants in GDF1 and PLD1 accounted for 74% of the contribution of RGs among 410 Ashkenazi Jewish probands. We identified genome-wide significant enrichment of RGs in C1orf127 , encoding a likely secreted protein expressed in embryonic mouse notochord and associated with laterality defects. Single-cell transcriptomes from gastrulation-stage mouse embryos revealed enrichment of RGs in genes highly expressed in the cardiomyocyte lineage, including contractility-related genes MYH6, UNC45B , MYO18B , and MYBPC3 in probands with left-sided CHD, consistent with abnormal contractile function contributing to these malformations. Genes with significant RG burden account for 1.3% of probands, more than half the inferred total. These results reveal the recessive contribution to CHD, and indicate that many genes remain to be discovered, with each likely accounting for a very small fraction of the total.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (39)
Weilai Dong
Department of Genetics, Yale School of Medicine
Sheng Chih Jin
Michael C. Sierant
Department of Genetics, Yale School of Medicine
Ziyu Lu
Boyang Li
Department of Mechanical Engineering and Materials Science
Qiongshi Lu
Department of Biostatistics and Medical Informatics, University of Wisconsin
Sarah U. Morton
Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital
Junhui Zhang
Francesc Lopez-Giraldez
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
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
James F. Cnota
Division of Cardiology, Cincinnati Children’s Hospital Medical Center
Michael Wagner
Deepak Srivastava
Daniel Bernstein
Department of Pediatrics, Cardiology, Stanford University
George A. Porter
Department of Pediatrics, Section of Cardiology, Yale School of Medicine
Jane Newburger
Department of Cardiology, Boston Children’s Hospital
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
Jonathan Seidman
Department of Genetics, Harvard Medical School
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
Richard P. Lifton
Laboratory of Human Genetics and Genomics, The Rockefeller University
Martina Brueckner
Department of Genetics, Yale School of Medicine