PROJECT SUMMARY/ABSTRACT Cleft palate (CP) is a common craniofacial structural birth defect caused by the incomplete closure of the palate (the structure separating the oral and nasal cavities), resulting in feeding, speech, and hearing problems. CP accounts for 33% of all orofacial clefts (OFCs) or approximately 1 in 1500 babies born worldwide. Although CP is colloquially used to refer to all types orofacial clefts (e.g. cleft lip or cleft with cleft palate), CP is embryologically and epidemiologically distinct from orofacial clefts involving the lip, suggesting a unique genetic etiology. The risk of CP recurrence in first degree relatives is over 50-fold higher than the population risk, suggesting a strong genetic component. However, there have been a dearth of genetic studies for CP. Three well-powered genome-wide association studies and meta-analysis have revealed only two associated loci, neither of which account for a large portion of the genetic heritability in any population. The lack of common variant associations suggest that the etiology of CP may be similar to other congenital anomalies, such as congenital heart disease, which often result from de novo mutations, inherited rare variants, and structural variation. We propose to elucidate the genetic architecture of CP by: (1) analyzing coding and noncoding de novo, inherited, and structural variants in whole genome sequencing of over 550 case-parent trios in a well-phenotyped, multi-ethnic cohort with CP; (2) integrating these data with transcriptomic data from mouse and human palate to identify pathways underlying specific CP subtypes; and (3) determine if CP risk variants/genes show pleiotropic effects in other birth defects and developmental disorders. This project is poised to rapidly advance our understanding of the genetic etiology of CP and translate risk to families, and may lead to improved diagnosis and treatment for individuals with CP.