Nonsyndromic cleft lip and palate (NSCLP) is a common birth defect affecting approximately 4,000 newborns each year in the US and a million worldwide. Multidisciplinary approaches have improved the care of these children but long-term problems persist and are related to facial dysmorphism and speech impediments. The health care costs are significant. Numerous studies support the idea that NSCLP is a complex disorder and that genetic factors play an important etiologic role in its development. The challenge now is to identify the NSCLP loci. Towards this goal, we have amassed a collection of multiplex families and simplex trios and we have employed a combination of candidate gene and genome scan approaches to successfully identify 12 chromosomal regions and several candidate genes to interrogate. Most exciting is the identification of a 20cM region on chromosome 8 with a maximum LOD score of 2.84 in a single large African-American family. In these continuing studies, we will further refine the identified chromosomal regions and fully characterize our candidate genes. We will continue to collect NSCLP families and simplex NSCLP trios to further expand our data set and will assemble a population based case-control data set for use in confirmatory studies. Finally we will submit our expanded sample set to a high-density genome scan during the third year of the funding cycle. The results of this study will provide data essential to the identification of the gene(s) contributing to the NSCLP phenotype. Identification of high-risk genotypes can lead to the development of prevention programs in selected populations and may suggest gene-based prevention strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE011931-11
Application #
7795240
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Harris, Emily L
Project Start
1999-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
11
Fiscal Year
2010
Total Cost
$355,773
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Leslie, Elizabeth J; Carlson, Jenna C; Shaffer, John R et al. (2017) Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate. Hum Genet 136:275-286
Leslie, Elizabeth J; Carlson, Jenna C; Shaffer, John R et al. (2017) Association studies of low-frequency coding variants in nonsyndromic cleft lip with or without cleft palate. Am J Med Genet A 173:1531-1538
Yuan, Qiuping; Zhao, Min; Tandon, Bhavna et al. (2017) Role of WNT10A in failure of tooth development in humans and zebrafish. Mol Genet Genomic Med 5:730-741
Ruegg, Teresa A; Cooper, Margaret E; Leslie, Elizabeth J et al. (2017) Ear Infection in Isolated Cleft Lip: Etiological Implications. Cleft Palate Craniofac J 54:189-192
Leslie, Elizabeth J; Liu, Huan; Carlson, Jenna C et al. (2016) A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3. Am J Hum Genet 98:744-54
Leslie, E J; Koboldt, D C; Kang, C J et al. (2016) IRF6 mutation screening in non-syndromic orofacial clefting: analysis of 1521 families. Clin Genet 90:28-34
Leslie, Elizabeth J; Carlson, Jenna C; Shaffer, John R et al. (2016) A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13. Hum Mol Genet 25:2862-2872
Swindell, Eric C; Yuan, Qiuping; Maili, Lorena E et al. (2015) Crispld2 is required for neural crest cell migration and cell viability during zebrafish craniofacial development. Genesis 53:660-7
Leslie, Elizabeth J; Taub, Margaret A; Liu, Huan et al. (2015) Identification of functional variants for cleft lip with or without cleft palate in or near PAX7, FGFR2, and NOG by targeted sequencing of GWAS loci. Am J Hum Genet 96:397-411
Cvjetkovic, Nevena; Maili, Lorena; Weymouth, Katelyn S et al. (2015) Regulatory variant in FZD6 gene contributes to nonsyndromic cleft lip and palate in an African-American family. Mol Genet Genomic Med 3:440-51

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