Abstract
Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains a challenge despite large-scale genomic sequencing efforts. We hypothesized that genetic determinants for CHDs may lie in protein interactomes of GATA4 and TBX5, two transcription factors that cause CHDs. Defining their interactomes in human cardiac progenitors via affinity purification-mass spectrometry and integrating results with genetic data from the Pediatric Cardiac Genomic Consortium revealed an enrichment of de novo variants among proteins that interact with GATA4 or TBX5. A consolidative score that prioritized interactome members based on variant, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied cardiac developmental genes, resulting in co-activation, and the GLYR1 missense variant associated with CHD disrupted interaction with GATA4. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating the contribution of genetic variants in disease.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
