Date of Graduation
5-2012
Document Type
Thesis (MS)
Program Affiliation
Genetic Counseling
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Jacqueline T. Hecht, PhD
Committee Member
Eric C. Swindell, PhD
Committee Member
John F. Teichgraeber, MD
Committee Member
Ariadne M. Letra, DDS, MS, PhD
Committee Member
Marianna Raia, MS, CGC
Abstract
Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect with a multifactorial etiology. Despite decades of research, the genetic underpinnings of NSCLP still remain largely unexplained. A genome wide association study (GWAS) of a large NSCLP African American family with seven affected individuals across three generations found evidence for linkage at 8q21.3-24.12 (LOD = 2.98). This region contained three biologically relevant candidate genes: Frizzled-6 (FZD6) (LOD = 2.8), Matrilin-2 (MATN2) (LOD = 2.3), and Solute Carrier Family 25, Member 32 (SLC26A32) (LOD = 1.6). Sequencing of the coding regions and the 5’ and 3’ UTRs of these genes in two affected family members identified a rare intronic variant, rs138557689 (c.-153+432A>C), in FZD6. The rs138557689/C allele segregated with the NSCLP phenotype; in silico analysis predicted and EMSA analysis showed that the 138557689/C allele creates new DNA binding sites. FZD6 is part of the WNT pathway, which is involved in craniofacial development, including midface development and upper lip fusion. Our novel findings suggest that an alteration in FZD6 gene regulation may perturb this tightly controlled biological pathway and in turn contribute to the development of NSCLP in this family. Studies are underway to further define how the rs138557689/C variant affects expression of FZD6.
Keywords
Frizzled 6 (FZD6), Matrilin 2 (MATN2), Solute Carrier Family 25, Member 32 (SLC26A32), candidate genes, nonsyndromic cleft lip and palate, rare variant