30% of patients with cleft lip and/or palate (CLP) have an associated syndrome, while 70% are clinically evaluated as non-syndromic3. Non-syndromic CLP patients are still at risk for other associated anomalies such as congenital heart disease (CHD). While the population incidence of CHD is under 1%, our group has shown that CHD incidence is 18% in non-syndromic cleft patients4. To our knowledge, this is the highest enrichment of CHD in any non-syndromic anatomic abnormality described. Our central hypothesis is that common molecular events underlie the development of the palate and the outflow tract of the heart in humans. Therefore, genetic defects that perturb these events result in concomitant CLP and CHD. Our long-term goal is to elucidate these developmental links and provide the foundation for a multigene panel that could improve diagnosis and treatment of CLP/CHD. Using mouse models of cleft, our group has shown that neural crest knockout of protein arginine methyl transferase-1(PRMT-1) results in simultaneous CLP and outflow tract CHD (e.g. truncus arteriosus, DORV and aortic arch defects). The objective of this study is to perform whole genome sequencing on ten case-trios of non-syndromic CLP patients with CHD. Potentially pathogenic genetic variants identified in our clinical cohort will be correlated with pathways perturbed in mice with a neural crest PRMT-1 knockout. This contribution is significant as it would help identify candidate genes for new genetic syndromes in humans and determine essential genes for screening in non-syndromic patients with CLP and CHD. The proposed research is directly relevant to the clinical and community research funding area, as it addresses mechanistic aspects of a novel seemingly unrelated but clinically co-existing group of lesions, is highly relevant to priorities of extra-mural funding agencies such as the NIH and AHA, and a multigene panel can be a significantly valuable clinical diagnostic tool.

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