Center for Craniofacial and Dental Genetics (CCDG): Genetics of Orofacial Clefts, Sub-types, and Subclinical Phenotypes - CIDR

The purpose of this project is to identify the genetic factors contributing to nonsyndromic orofacial clefts (OFCs), common subtypes, and related subclinical phenotypes. The most common subtypes of OFCs are cleft lip alone (CL), cleft lip with cleft palate (CLP), and cleft palate alone (CP). CL and CLP can be unilateral (left or right) or bilateral. Related subclinical phenotypes include occult lip muscle defects, characteristics of craniofacial morphology, and subtle speech abnormalities, which are distributed within families of affected individuals, and may reflect the underlying genetic susceptibility revealing clues about OFC etiology. The multi-ethnic dataset comprises participants recruited from Pennsylvania, Puerto Rico, Colombia, Philippines, Nigeria, and Ghana, and includes individuals with OFCs (cases), their unaffected relatives, and unrelated healthy controls. The specific aims of this project are to perform genome-wide association (GWAS) scans of (1) OFCs, (2) cleft subtypes (CL, CLP, CP, and laterality subtypes), and (3) cleft-associated subclinical phenotypes to identify variants associated with manifestations across the cleft-risk spectrum. Phenotyping for participants involved characterization of the overt clefts in cases, including affected structures (lip, alveolus, hard and soft palates), visible microforms, completeness, and laterality. Individuals with syndromic forms of OFCs were excluded from participation. Subclinical features were collected for all participants, including unaffected relatives and controls. Orbicularis oris (upper lip muscle) defects were assessed by high-resolution ultrasonography and scored by three independent raters. Lip print patterns were assessed by digital photography and scored for paramedical whorls by three independent raters. Velopharyngeal insufficiency was assessed with perceptual screening by a speech-language pathology expert. This dataset has potential to improve knowledge of the genetic contributors to OFCs, subtypes, and associated subclinical phenotypes by facilitating genetic association discovery, meta-analysis, and replication efforts. Findings may ultimately be useful for predicting OFC risk and recurrence, and may enhance our understanding of OFC biology. ]]>
Included are individuals affected with orofacial clefts (cleft lip, cleft lip with cleft palate, and cleft palate), their affected and unaffected relatives, and controls with no personal or family history of craniofacial anomalies.]]>
Although orofacial clefts are the most common craniofacial birth defect, affecting approximately 1 in 700 newborns, there are still major gaps in our understanding of cleft etiology. Investigation of the genetics/genomics of orofacial clefts has been a major focus of the Center for Craniofacial and Dental Genetics at the University of Pittsburgh (CCDG) ever since it was established in 2001, but our studies of orofacial clefts began much earlier. Dr. Marazita and her colleagues have been investigating the epidemiology and genetics of orofacial clefting since the mid-1980s. Since the late 1990s, the CCDG, with the help of our extensive network of collaborators, has been collecting detailed phenotypic and genomic data on families with a history of orofacial clefting from around the globe. We have made significant progress in mapping genes for many of the major cleft subtypes and have now identified some of the first functional variants through animal and cell experiments. A key aspect of our approach is deep phenotyping, where we move beyond the tradition phenotypic definitions of clefting to focus on incorporating subclinical traits (e.g., subtle abnormalities in speech and oral and facial structures) distributed within affected families. Such subclinical phenotypes can reveal clues about etiology, eventually allowing translation of our findings into strategies that can be assessed through robust clinical studies, with the ultimate goal of improving the standard of care of individuals with clefts. Major Findings To Date: Uncovered the role of IRF6 in non-syndromic clefting, and many other genes Conducted the most comprehensive multiethnic GWAS of clefting Identified the first genome-wide associated variant for isolated cleft palate Performed the first GWAS of velopharyngeal dysfunction Identified some of the first confirmed functional variants for orofacial clefting Performed the first targeted sequencing study of known GWAS hits Received multiple rounds of funding for whole genome-sequencing of orofacial cleft trios through the Gabriel Miller Kids First Initiative Published a more than 180 peer-reviewed paper to date related to orofacial cleft genetics and phenomics ]]>