Clefts of the lip and/or palate are common human birth defects that require substantial surgical, dental, speech, and behavioral interventions and impose economic and societal burdens. While there are many rare causes of clefting disorders, approximately 70% are isolated or nonsyndromic and the result of a complex interplay of genegene and gene-environment interactions. After more than a decade of etiologic investigations with relatively modest advances, the last two years has seen the field become excitingly dynamic. We have recently demonstrated significant contributions by the MSX1, FGFR1, and IRF6 genes to cases of nonsyndromic clefting and have just completed the first two of a three stage genome-wide search to identify genes for clefts. Linkage analysis has found three novel high probability loci (6q, 8p, gq) in 217 families with genotyping almost complete on an additional 53 families. One locus, on 9q, has a LOD of 6.6. Coupling these successes to a realistic capacity for high throughput genotyping and powerful new statistical approaches affords the opportunity to characterize genetic and gene-environmental causes of clefting with unprecedented power and resolution. In this proposal we will use a large collection of families (over 330) and case parent triads (over 950) from the Philippines as a core resource for genome wide linkage and disequilibrium studies. We supplement this core collection with collaborative access to over 600 families for linkage and over 2000 triads with extensive environmental exposure data.
The specific aims of this proposal will use candidate gene rankings based on global human gene expression analysis to assist in fine mapping and gene identification. Dense SNP maps will be combined with conserved sequence elements identified by multiple species comparisons to select the best regions in which to begin mutation searches. Genes/mutations that are likely to be etiologic will undergo additional genetic evaluation and functional analysis. Characterization of genomic rearrangements will provide an adjunct to gene finding. Discovered genes will then be used in studies of gene-gene and gene-environment interactions. The outcome of this project will be immediate and direct contributions to understanding genetic aspects of clefting and far better insights into the basic biology of craniofacial development. It will confirm proof of principle that complex human birth defects can be understood, and diagnosis and prevention improved.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DE008559-21
Application #
7918954
Study Section
Special Emphasis Panel (NSS)
Program Officer
Harris, Emily L
Project Start
1988-07-01
Project End
2014-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
21
Fiscal Year
2010
Total Cost
$719,654
Indirect Cost
Name
University of Iowa
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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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
Bureau, Alexandre; Begum, Ferdouse; Taub, Margaret A et al. (2018) Inferring disease risk genes from sequencing data in multiplex pedigrees through sharing of rare variants. Genet Epidemiol :
Eshete, M A; Liu, H; Li, M et al. (2018) Loss-of-Function GRHL3 Variants Detected in African Patients with Isolated Cleft Palate. J Dent Res 97:41-48
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
Cox, Liza L; Cox, Timothy C; Moreno Uribe, Lina M et al. (2018) Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate. Am J Hum Genet 102:1143-1157
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; Standley, Jennifer; Petrin, Aline et al. (2017) Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes. Genet Epidemiol 41:887-897
Liu, Huan; Busch, Tamara; Eliason, Steven et al. (2017) Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate. Birth Defects Res 109:27-37

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