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. LiftonChristine E. Seidman, Wendy K. Chung, Martin Tristani-Firouzi, H. Joseph Yost, Avi Ma'ayan, Bruce D. Gelb

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish
Pages (from-to)376-386
Number of pages11
JournalJACC: Basic to Translational Science
Volume5
Issue number4
DOIs
StatePublished - Apr 2020

Keywords

  • congenital heart disease
  • systems biology
  • translational genomics

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