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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZRG1-GGG-E (03))
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Harris, Emily L
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University of Texas Health Science Center Houston
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United States
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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
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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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