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Kids First: Genomics of Isolated Cleft Lip

Isolated Cleft Lip (CL, Human Phenotype Ontology # HP0100335) is a subtype within Orofacial Clefts (OFC, HP0000202) birth defects. OFCs can involve gaps in the lip, alveolus and/or the hard or soft palate. Developmental origins of the affected structures, epidemiology, and familial patterns of CL versus other OFCs suggest some common risk factors, but emerging evidence emphasizes that these subtypes also have unique risk factors.

Isolated CL has seldom been investigated separately in genetic studies. Early studies using microsatellite markers prior to the availability of SNP chips found differences in CL families versus other cleft subtypes, notably reporting increased association with certain IRF6 variants in CL families versus other cleft types. With the advent of SNP chips, some studies addressed CL, e.g. genome-wide association of CL was seen with TPM1 and NOG and 9q21.32. We have performed some of the only genome-wide association studies (GWAS) to compare and contrast CL and Cleft Lip with Cleft Palate (CLP). We find evidence that CL and CLP have some distinct genetic risk factors, differences in strength or direction of effects between CL and CLP, and modifying loci that predispose specifically for CL over CLP. Some loci are most-significant in families where all affected members had CL. Modifiers of cleft lip laterality and side of the cleft were more successful in CL than in CLP and the loci identified in CL had no detectable effect in CLP, reinforcing the idea that CL and CLP have distinct risk factors. An overall conclusion from these studies is that CL appears more genetically homogeneous than does CLP, thus highlighting the importance of subtype and family type inclusion in studies of OFCs. Importantly, the homogeneity of CL makes it more amenable to gene discovery in the moderate sample sizes available with whole genome sequencing (WGS).

The current project builds upon the GWAS and WGS analyses by our group and others. The WGS data generated will be used to discover new loci for CL, to replicate/prioritize previously published loci, and to aid in determining CL-specific causal genes/alleles. Short Read WGS data available for 1903 individuals include 629 affected probands: 553 CL and 40 CLP (with CL relatives) complete trios, 29 CL and 1 CLP dyads, and 5 CL and 1 CLP singletons. Of the 1903 total individuals, 554 are of European descent, 381 Central/South American descent, 857 of Asian descent, 7 of African descent, and 104 are race other/unknown.

With our phenotypic data plus the WGS, we will be able to find new loci, gain better understanding of how risk related to those loci differs across populations, create the knowledge needed to choose loci for follow-up functional studies, build the knowledge needed for accurate risk predictions, and ultimately set the stage for translation into clinical practice.

Study Population: The individuals and families utilized in this project were recruited through the Pittsburgh Orofacial Cleft study (POFC) involved research collaborations world-wide coordinated by the Center for Craniofacial and Dental Genetics of the University of Pittsburgh (CCDG). Extensive information is available for many of these trios, including sex, self-reported race and ethnicity, birth date and age at enrollment, phenotypes for affected cases (i.e. extensive detail on the OFC defect in terms of type, laterality, completeness), phenotypes for all affected and unaffected family members (including facial measurements, lip morphology, dental characteristics and many more), vital status and age at last known vital status, clinical information (e.g. surgical and medical history for all affected cases, some limited systems review for unaffected family members), and family medical history (e.g., family history of cancer and birth defects).

Molecular Technology: Short Read WGS

Data Available:

  1. Demographics (site, age, sex, race, ethnicity)
  2. Cleft details
  3. Family level cleft details (i.e. multiplex, clefting maternal side, clefting paternal side, or both)
  4. Height/Weight
  5. Pregnancy Exposures data (birth height, birth weight, smoking, vitamins, alcohol, epilepsy, gestational diabetes) for 3 months prior to first trimester and first trimester.
  6. Subject_IDs from other sequencing studies
  7. Data use limitations from the consents

The remaining phenotypic/medical/image data for this study are available through FaceBase (facebase.org): DOI: 10.25550/5A-FJBJ and DOI: 10.25550/56-ES6P.