Author + information
- Received November 19, 2019
- Revision received January 23, 2020
- Accepted January 24, 2020
- Published online April 27, 2020.
- Jonathan J. Edwards, MDa,
- Andrew D. Rouillard, PhDb,
- Nicolas F. Fernandez, PhDb,
- Zichen Wang, PhDb,
- Alexander Lachmann, PhDb,
- Sunita S. Shankaran, PhDc,
- Brent W. Bisgrove, PhDd,
- Bradley Demarest, MSd,
- Nahid Turan, PhDe,
- Deepak Srivastava, MDf,
- Daniel Bernstein, MDg,
- John Deanfield, MDh,
- Alessandro Giardini, MD, PhDh,
- George Porter, MD, PhDi,
- Richard Kim, MDj,
- Amy E. Roberts, MDk,
- Jane W. Newburger, MD, MPHk,
- Elizabeth Goldmuntz, MDl,
- Martina Brueckner, MDm,
- Richard P. Lifton, MD, PhDm,n,
- Christine E. Seidman, MDo,p,q,
- Wendy K. Chung, MD, PhDr,s,
- Martin Tristani-Firouzi, MDt,
- H. Joseph Yost, PhDd,
- Avi Ma’ayan, PhDb and
- Bruce D. Gelb, MDu,v,∗ ()
- aDepartment of Pediatrics, Division of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- bDepartment of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, LINCS-BD2K DCIC, Icahn School of Medicine at Mount Sinai, New York, New York
- cDepartment of Molecular Physiology and Biophysics, Vanderbilt School of Medicine, Nashville, Tennessee
- dMolecular Medicine Program, University of Utah School of Medicine, Salt Lake City, Utah
- eCoriell Institute, Camden, New Jersey
- fGladstone Institute of Cardiovascular Disease, San Francisco, California
- gDivision of Pediatric Cardiology, Stanford University School of Medicine, Stanford University, Stanford, California
- hDepartment of Cardiology, Great Ormond Street Hospital, University College London, London, United Kingdom
- iDepartment of Pediatrics, University of Rochester Medical Center, University of Rochester School of Medicine and Dentistry, Rochester, New York
- jSection of Cardiothoracic Surgery, Keck School of Medicine of USC, University of Southern California, Los Angeles, California
- kDepartment of Cardiology, Children's Hospital Boston, Boston, Massachusetts
- lDepartment of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- mDepartment of Genetics, Yale School of Medicine, New Haven, Connecticut
- nHoward Hughes Medical Institute, Yale University, New Haven, Connecticut
- oDepartment of Genetics, Harvard Medical School, Boston, Massachusetts
- pHoward Hughes Medical Institute, Harvard University, Boston, Massachusetts
- qCardiovascular Division, Brigham and Women’s Hospital, Harvard University, Boston, Massachusetts
- rDepartment of Pediatrics, Columbia University Medical Center, New York, New York
- sDepartment of Medicine, Columbia University Medical Center, New York, New York
- tNora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah School of Medicine, Salt Lake City, Utah
- uMindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- vDepartment of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York
- ↵∗Address for correspondence:
Dr. Bruce D. Gelb, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1040, New York, New York 10029.
• Combining CHD phenotype–driven gene set enrichment and CRISPR knockdown screening in zebrafish is an effective approach to identifying novel CHD genes.
• Mutations affecting genes coding for the WAVE2 protein complex and small GTPase-mediated signaling are associated with LVOTO lesions.
• WAVE2 complex genes brk1, nckap1, and wasf2 and regulators of small GTPase signaling cul3a and racgap1 are critical to zebrafish heart development.
Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development.
This work was supported by a grant from the National Center for Research Resources and the National Center for Advancing Translational Sciences (U01 HL098153), National Institutes of Health grants to the Pediatric Cardiac Genomics Consortium (U01-HL098188, U01-HL098147, U01-HL098153, U01-HL098163, U01-HL098123, U01-HL098162, and U01-HL098160), and the National Institutes of Health Centers for Mendelian Genomics (5U54HG006504). Dr. Edwards was supported by National Institutes of Health Grant No. 5T32HL007915. Drs. Lifton and Seidman were supported by the Howard Hughes Medical Institute. Dr. Chung was supported by the Simons Foundation. Dr. Srivastava is co-founder and has served on the scientific advisory board for Tenaya Therapeutics. Dr. Lifton is director of Roche; has served on the scientific advisory board for Regeneron; and has served as a consultant for Johnson and Johnson. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received November 19, 2019.
- Revision received January 23, 2020.
- Accepted January 24, 2020.
- 2020 The Authors