Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common complex orofacial birth defect associated with significant morbidity and increased mortality. Surgical correction is always required and the multidisciplinary health interventions cost approximately a half billion dollars each year. Candidate gene studies and GWAS have identified a number of putative NSCLP genes and loci that are estimated to account for only ~20% of the genetic variation. While this represents an important starting point, the majority of genetic risk for NSCLP remains undiscovered and represents a frontier to be explored. We have used both candidate gene and GWAS approaches to define genetic variation in NSCLP;a previously unsuspected gene, CRISPLD2, was found to be associated with NSCLP and, when knocked down in zebrafish, causes palatal and jaw abnormalities. The goal of this project is to continue identifying and understanding the undiscovered variation that contributes to the genetic architecture of NSCLP. To accomplish this goal, we will apply the newest technologies, whole exome next generation sequencing (WES) and chromosomal microarray analysis (CMA) to our well-characterized extensive family-based NSCLP dataset. We will use the WES that detects coding and noncoding variants (Agilent 50Mb v.4 exon content +UTR) because we have shown that both types of variation contribute to NSCLP. In addition, CMA will detect copy number variants (CNVs) that would be missed by WES. This will provide the most complete coverage and the family-based design will allow for detection familial causes of NSCLP. Candidate genes will be prioritized, functionally tested in zebrafish to determine biological significance and analyzed in our case controls for spectrum variation and risk modeling. The results will provide important information about risk variants, individually and in aggregate. During the entire study period, we will continue to expand our NSCLP dataset for this and future genetic studies. Application of the newest technology to our extensive family-based dataset is a powerful method for uncovering the genetic variation contributing to this common birth defect. This approach is a significant step forward;the results will add important new information to the developing knowledge base of genetic variation responsible for NSCLP, which will translate into genetic counseling for at-risk families.

Public Health Relevance

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect affecting 4000 newborns in the US and 135,000 worldwide each year. The etiology is poorly understood and currently, only 20% of the NSCLP genetic liability has been identified, limiting our ability to identify at-risk individuals or provide accurate counselin for families. In these studies, we apply the newest technology to identify the genetic variation underlying NSCLP in families with multiple cases, will test the variants for expression and functionality in a fish model and develop ethnic-specific risks. The results of this study will ultimately be utilized to identify and test for potential at-risk genotypes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE011931-13
Application #
8460388
Study Section
Special Emphasis Panel (ZRG1-GGG-E (03))
Program Officer
Harris, Emily L
Project Start
1999-04-01
Project End
2017-11-30
Budget Start
2012-12-26
Budget End
2013-11-30
Support Year
13
Fiscal Year
2013
Total Cost
$760,204
Indirect Cost
$94,981
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, 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
Ruegg, Teresa A; Cooper, Margaret E; Leslie, Elizabeth J et al. (2015) Ear Infection in Isolated Cleft Lip: Etiological Implications. Cleft Palate Craniofac J :
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
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
Letra, Ariadne; Maili, Lorena; Mulliken, John B et al. (2014) Further evidence suggesting a role for variation in ARHGAP29 variants in nonsyndromic cleft lip/palate. Birth Defects Res A Clin Mol Teratol 100:679-85
Letra, A; Zhao, M; Silva, R M et al. (2014) Functional Significance of MMP3 and TIMP2 Polymorphisms in Cleft Lip/Palate. J Dent Res 93:651-6
Letra, Ariadne; Silva, Renato M; Motta, Luise G et al. (2012) Association of MMP3 and TIMP2 promoter polymorphisms with nonsyndromic oral clefts. Birth Defects Res A Clin Mol Teratol 94:540-8
Yuan, Qiuping; Chiquet, Brett T; Devault, Laura et al. (2012) Craniofacial abnormalities result from knock down of nonsyndromic clefting gene, crispld2, in zebrafish. Genesis 50:871-81

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