Orofacial clefts (OFCs), particularly nonsyndromic cleft lip with or without cleft palate (NS CL/P) are a major public health problem, affecting one in every 500-1000 births worldwide. Therefore, many research groups have attempted to identify genetic loci contributing to the etiology of CL/P, with some recent successes by our research group and others. It appears that the genetic contribution to the etiology of oral-facial clefting is complex, probably heterogeneous, and probably due to interacting effects of multiple loci in some cases. The current proposal is a competing continuation of grant #1-R01-DE016148 that had the goal of identifying extended phenotypic features that represent either subclinical phenotypic manifestations of CL/P genes or additional expression of CL/P genes. We successfully completed the specific aims of (1) ascertaining and phenotyping families from Pittsburgh and St. Louis, (2) identifying endophenotypes, notably orbicularis oris (OO: upper lip) muscle defects and lip print whorls in affected and unaffected members of the multiplex CL/P families;(3) identifying candidate genes for the endophenotypes (BMP4 for OO defects and IRF6 for lip print whorls), (4) performing other genetic analyses of CL/P and the endophenotypes. Now that we have good evidence for the significance of these phenotypic features in multiplex CL/P families, the major goals of this competing continuation are (1) to investigate these features in general NS CL/P families (i.e., simplex as well as multiplex, plus in other ethnicities) in order to determine the potential clinical relevance of these phenotypes;(2) to investigate further how these features can clarify the observed penetrance patterns of CL/P in families;and (3) to perform candidate gene, genome-wide linkage, and genome-wide association studies to identify genes related to the extended phenotypic features. To reach these goals nuclear families, extended multiplex kindreds and twin pairs will be ascertained in Pittsburgh, St. Louis, Texas, and Denmark. All participants will be assessed for the following features: OO muscle anatomy by high-resolution ultrasound, dermatoglyphic lip and finger prints, craniofacial measurements from 3D images, handedness and other laterality traits, minor physical anomalies, and velopharyngeal competence via perceptual speech screening. SNPs in candidate genes (BMP4, IRF6) and regions (6q, 9q) will be genotyped, as will a dense genome-wide SNP panel, followed by statistical genetic analyses. Positive genetic findings will be followed by additional fine-mapping and/or mutational screens.
This project will identify physical features (phenotypes) associated with cleft lip and palate birth defects, and will identify genes related to these phenotypes. This knowledge will lead to improved genetic counseling in families with cleft lip and palate, and also will eventually lead to improved therapies for these very common birth defects.
| Oseni, Ganiyu O; Jain, Deepti; Mossey, Peter A et al. (2018) Identification of paternal uniparental disomy on chromosome 22 and a de novo deletion on chromosome 18 in individuals with orofacial clefts. Mol Genet Genomic Med 6:924-932 |
| Roosenboom, Jasmien; Lee, Myoung Keun; Hecht, Jacqueline T et al. (2018) Mapping genetic variants for cranial vault shape in humans. PLoS One 13:e0196148 |
| Larson, Jacinda R; Manyama, Mange F; Cole, Joanne B et al. (2018) Body size and allometric variation in facial shape in children. Am J Phys Anthropol 165:327-342 |
| Howe, Laurence J; Lee, Myoung Keun; Sharp, Gemma C et al. (2018) Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology. PLoS Genet 14:e1007501 |
| Claes, Peter; Roosenboom, Jasmien; White, Julie D et al. (2018) Genome-wide mapping of global-to-local genetic effects on human facial shape. Nat Genet 50:414-423 |
| Shaffer, John R; LeClair, Jessica; Carlson, Jenna C et al. (2018) Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts. Am J Med Genet A : |
| Carlson, Jenna C; Nidey, Nichole L; Butali, Azeez et al. (2018) Genome-wide interaction studies identify sex-specific risk alleles for nonsyndromic orofacial clefts. Genet Epidemiol 42:664-672 |
| Chernus, Jonathan; Roosenboom, Jasmien; Ford, Matthew et al. (2018) GWAS reveals loci associated with velopharyngeal dysfunction. Sci Rep 8:8470 |
| Gowans, Lord Jephthah Joojo; Oseni, Ganiyu; Mossey, Peter A et al. (2018) Novel GREM1 Variations in Sub-Saharan African Patients With Cleft Lip and/or Cleft Palate. Cleft Palate Craniofac J 55:736-742 |
| Fu, Jack M; Leslie, Elizabeth J; Scott, Alan F et al. (2018) Detection of de novo copy number deletions from targeted sequencing of trios. Bioinformatics : |
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