Developmental and genetic function of SHROOM3

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PROJECT SUMMARY Congenital heart disease (CHD) is the most common cause of death due to birth defects. Despite its frequency, identifying genetic causes of CHD has been challenging. Mendelian inheritance of sporadic (nonsyndromic) CHD is rare. Instead, the genetic architecture of CHD is characterized by non-penetrance, variable expressivity, and likely oligogenic effects. Although genome wide association studies, trio, and family-based studies have been utilized, there has been little emphasis on examining epistasis, additive effects, or mutational burden. Furthermore, although an improved understanding of cardiac development has identified genes and pathways that underlie CHD in animal models, this knowledge has not always translated readily into an understanding of disease causation in human CHD. In order to improve our ability to predict risk for CHD and prognosis, it is important to identify new genes and pathways that contribute to sporadic CHD and integrate functional genomics for variant analysis with developmental biology for mechanistic understanding. We propose to address these critical needs through investigation of a novel gene causing cardiac malformations, SHROOM3, and delineation of its interactome, as an exemplar leveraging human genomics and developmental biology. The aims of this study are to: 1) test the hypothesis that cardiogenesis requires SHROOM3 interaction with planar cell polarity (PCP) proteins and downstream effectors. The outcome of this aim will identify cell- and tissue-specific consequences of loss of Shroom3, identify its interactome and consequence of its genetic interactions on CHD; and 2) test the hypothesis that rare variants in genes encoding PCP signaling and downstream effector proteins are enriched in patients with CHD. The outcome of this aim will functionally validate SHROOM3 rare variants and identify genes and pathways important for the susceptibility to CHD. Using a combination of functional genomics to define the impact of rare variants, mechanistic studies using mouse models, and human genetics, these studies will collectively define the role of SHROOM3 in heart development and the contribution of SHROOM3 and PCP pathway members to the genetic architecture of CHD.