The specific aim of the investigations described in this proposal is to define molecular mechanisms that cause, or predispose, to non-syndromic cleft lip with/without cleft palate (NSCLP). NSCLP is one of the most common birth defects with a prevalence of approximately 1 in 1000 live births. The etiology of this disorder has been unclear although recently there is evidence of genetic etiology. The applicant has reported evidence of linkage between familial NSCLP and BCL3 gene on chromosome 19 in 17 of 39 families, and states that she is in a unique position to accomplish the goals because her lab has characterized 60 families with NSCLP, the technology for genomic mapping is now mature, and that a number of biologically relevant candidate genes have been identified. The current application describes experiments aimed at identification of new multiplex and simples families with NSCLP, and to map genetic loci causing NSCLP using both candidate gene approaches and a genome wide approach with the Weber-CHLC screening set of PCR based markers (version 8). The plan is to study at least 42 candidate genes that may possibly have a role in craniofacial embryogenesis as well as random gnomic markers. Both non-perimetria and perimetria statistical methods will be used to optimize linkage detection and markers of candidate genes are to be identified. Family studies will be tested to confirm or exclude linkage in two ethnically diverse populations. One of the aims is to follow up on prior data in which 17 families were linked to the BCL locus by performing mutation analysis at BCL3 in the subset of families with evidence of linkage with cleft lip and palate to BCL3.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral Biology and Medicine Subcommittee 1 (OBM)
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University of Texas Health Science Center Houston
Schools of Medicine
United States
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Rodriguez, Nicholas; Maili, Lorena; Chiquet, Brett T et al. (2018) BRCA1 and BRCA2 gene variants and nonsyndromic cleft lip/palate. Birth Defects Res 110:1043-1048
Chiquet, Brett T; Yuan, Qiuping; Swindell, Eric C et al. (2018) Knockdown of Crispld2 in zebrafish identifies a novel network for nonsyndromic cleft lip with or without cleft palate candidate genes. Eur J Hum Genet 26:1441-1450
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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

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