SUMMARY Orofacial clefts (OFCs) are the most common craniofacial congenital anomalies and can be categorized into two large groups: cleft of the upper lip with or without a cleft palate (CL/P) and cleft palate only (CP). These birth defects are easily recognizable, and although the long-term prognosis is favorable with intervention, affected individuals typically undergo multiple surgical procedures, may have abnormal dentition, recurrent ear infections, speech and hearing problems, and have higher rates of morbidity and mortality later in life. Despite sharing a defect of the palate, CP and CL/P are considered etiologically distinct. It is evident that both CP and CL/P are highly heritable, and while dozens of well-established genetic risk loci have been identified for CL/P, only a few loci have been identified for CP. Historically, these studies have evaluated CP cases as a whole, rather than by stratifying by the subtypes of CP that are defined by the part of the palate that is affected. Thus, the relative lack of common variants may be due to genetic heterogeneity among phenotypic subtypes which dilutes the ability to detect associated variants when evaluated together. Alternatively, and/or concurrently, CP etiology may be more closely aligned with that of other structural birth defects, such as congenital heart disease, which often result from de novo mutations (DNMs) and inherited rare variants of large effect sizes. To elucidate the genetic architecture of CP in the context of these possibilities, I will utilize whole genome sequencing (WGS) data from a cohort of 518 CP cases consisting primarily of case-parent trios, and encompassing diverse populations and all subtypes of CP by 1) evaluation of the genetic heterogeneity of CP subtypes for common and rare variants utilizing biologically relevant genes from transcriptomic data of the embryonic mouse palate and 2) identification of rare variants segregating with disease in multiplex families, followed by investigation of segregating variants in the full cohort. The trio-based nature of this cohort is particularly useful for discovery as it allows for common and rare variant analysis by transmission disequilibrium tests, which are robust to population stratification, as well as identification of high confidence DNMs. To further maximize discovery power, these analyses will be focused on coding variants that meet specific criteria for pathogenicity prediction to best prioritize potentially causal variants. Upon completion of this research, our understanding of the genetic risks for CP and each of the subtypes will be significantly advanced. Knowledge of novel risk factors will not only improve prediction, prevention, and prognosis of CP, but also elucidate mechanisms of normal and abnormal palatal development.