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.

中文翻译：

---

蛋白质相互作用网络与先天性心脏病变体的整合揭示了候选疾病的基因

先天性心脏病（CHD）存在于1％的活产中，但是尽管进行了大规模的基因组测序工作，但因果突变的鉴定仍然是一个挑战。我们假设CHD的遗传决定因素可能位于GATA4和TBX5的蛋白质​​相互作用组中，这是导致CHD的两个转录因子。通过亲和纯化-质谱法在人类心脏祖细胞中定义它们的相互作用基因，并将结果与​​儿科心脏基因组学联盟的遗传数据相结合，揭示了与GATA4或TBX5相互作用的蛋白质中从头变异体的富集。一项基于变体，基因和先证者特征对相互作用组成员进行优先排序的综合评分确定了可能引起CHD的基因，包括表观遗传阅读器GLYR1。GLYR1和GATA4共同占据了心脏发育基因，导致共激活，并且与CHD相关的GLYR1错义变体破坏了与GATA4的相互作用。这种蛋白质组学和遗传学综合方法为优先考虑和询问疾病中遗传变异的作用提供了框架。