Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects

Jonathan J Edwards; Andrew D Rouillard; Nicolas F Fernandez; Zichen Wang; Alexander Lachmann; Sunita S Shankaran; Brent W Bisgrove; Bradley Demarest; Nahid Turan; Deepak Srivastava; Daniel Bernstein; John Deanfield; Alessandro Giardini; George Porter; Richard Kim; Amy E Roberts; Jane W Newburger; Elizabeth Goldmuntz; Martina Brueckner; Richard P Lifton; Christine E Seidman; Wendy K Chung; Martin Tristani-Firouzi; H Joseph Yost; Avi Ma'ayan; Bruce D Gelb

doi:10.1016/j.jacbts.2020.01.012

Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects

JACC Basic Transl Sci. 2020 Apr 8;5(4):376-386. doi: 10.1016/j.jacbts.2020.01.012. eCollection 2020 Apr.

Authors

Jonathan J Edwards¹, Andrew D Rouillard², Nicolas F Fernandez², Zichen Wang², Alexander Lachmann², Sunita S Shankaran³, Brent W Bisgrove⁴, Bradley Demarest⁴, Nahid Turan⁵, Deepak Srivastava⁶, Daniel Bernstein⁷, John Deanfield⁸, Alessandro Giardini⁸, George Porter⁹, Richard Kim¹⁰, Amy E Roberts¹¹, Jane W Newburger¹¹, Elizabeth Goldmuntz¹², Martina Brueckner¹³, Richard P Lifton^{13

14}, Christine E Seidman^{15

16

17}, Wendy K Chung^{18

19}, Martin Tristani-Firouzi²⁰, H Joseph Yost⁴, Avi Ma'ayan², Bruce D Gelb^{21

22}

Affiliations

¹ Department of Pediatrics, Division of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
² Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, LINCS-BD2K DCIC, Icahn School of Medicine at Mount Sinai, New York, New York.
³ Department of Molecular Physiology and Biophysics, Vanderbilt School of Medicine, Nashville, Tennessee.
⁴ Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, Utah.
⁵ Coriell Institute, Camden, New Jersey.
⁶ Gladstone Institute of Cardiovascular Disease, San Francisco, California.
⁷ Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford University, Stanford, California.
⁸ Department of Cardiology, Great Ormond Street Hospital, University College London, London, United Kingdom.
⁹ Department of Pediatrics, University of Rochester Medical Center, University of Rochester School of Medicine and Dentistry, Rochester, New York.
¹⁰ Section of Cardiothoracic Surgery, Keck School of Medicine of USC, University of Southern California, Los Angeles, California.
¹¹ Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts.
¹² Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
¹³ Department of Genetics, Yale School of Medicine, New Haven, Connecticut.
¹⁴ Howard Hughes Medical Institute, Yale University, New Haven, Connecticut.
¹⁵ Department of Genetics, Harvard Medical School, Boston, Massachusetts.
¹⁶ Howard Hughes Medical Institute, Harvard University, Boston, Massachusetts.
¹⁷ Cardiovascular Division, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts.
¹⁸ Department of Pediatrics, Columbia University Medical Center, New York, New York.
¹⁹ Department of Medicine, Columbia University Medical Center, New York, New York.
²⁰ Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah School of Medicine, Salt Lake City, Utah.
²¹ Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
²² Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.

Abstract

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.

Keywords: CHD, congenital heart disease; CORUM, Comprehensive Resource of Mammalian Protein Complexes; CRISPR, clustered regularly interspaced short palindromic repeats; CTD, conotruncal defect; GOBP, Gene Ontology biological processes; HHE, high heart expression; HLHS, hypoplastic left heart syndrome; HTX, heterotaxy; LVOTO, left ventricular outflow tract obstruction; MGI, Mouse Genome Informatics; PCGC, Pediatric Cardiac Genomics Consortium; PPI, protein-protein interaction; congenital heart disease; systems biology; translational genomics.

Abstract

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