TY - JOUR
T1 - Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects
AU - Edwards, Jonathan J.
AU - Rouillard, Andrew D.
AU - Fernandez, Nicolas F.
AU - Wang, Zichen
AU - Lachmann, Alexander
AU - Shankaran, Sunita S.
AU - Bisgrove, Brent W.
AU - Demarest, Bradley
AU - Turan, Nahid
AU - Srivastava, Deepak
AU - Bernstein, Daniel
AU - Deanfield, John
AU - Giardini, Alessandro
AU - Porter, George
AU - Kim, Richard
AU - Roberts, Amy E.
AU - Newburger, Jane W.
AU - Goldmuntz, Elizabeth
AU - Brueckner, Martina
AU - Lifton, Richard P.
AU - Seidman, Christine E.
AU - Chung, Wendy K.
AU - Tristani-Firouzi, Martin
AU - Yost, H. Joseph
AU - Ma'ayan, Avi
AU - Gelb, Bruce D.
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2020 The Authors
PY - 2020/4
Y1 - 2020/4
N2 - 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.
AB - 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.
KW - congenital heart disease
KW - systems biology
KW - translational genomics
UR - http://www.scopus.com/inward/record.url?scp=85083390164&partnerID=8YFLogxK
U2 - 10.1016/j.jacbts.2020.01.012
DO - 10.1016/j.jacbts.2020.01.012
M3 - Article
AN - SCOPUS:85083390164
SN - 2452-302X
VL - 5
SP - 376
EP - 386
JO - JACC: Basic to Translational Science
JF - JACC: Basic to Translational Science
IS - 4
ER -