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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
3R01DE016148-08S1
Application #
8802910
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Harris, Emily L
Project Start
2004-08-12
Project End
2014-09-30
Budget Start
2014-03-01
Budget End
2014-09-30
Support Year
8
Fiscal Year
2014
Total Cost
$490,000
Indirect Cost
$170,037
Name
University of Pittsburgh
Department
Dentistry
Type
Schools of Dentistry
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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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

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