Regulatory variant in FZD6 gene contributes to nonsyndromic cleft lip and palate in an African-American family

摘要: Nonsyndromic cleft lip with or without palate (NSCLP) is a common birth defect affecting 135,000 newborns worldwide each year. While multifactorial etiology has been suggested as the cause, despite decades of research, genetic underpinnings NSCLP remain largely unexplained. In our previous genome-wide linkage study large African-American family, we identified candidate locus at 8q21.3-24.12 (LOD = 2.98). This region contained four genes, Frizzled-6 (FZD6), Matrilin-2 (MATN2), Odd-skipped related 2 (OSR2) and Solute Carrier Family 25, Member 32 (SLC25A32). FZD6 was located under maximum peak. this study, sequenced coding noncoding regions these genes in two affected family members, rare variant intron 1 (rs138557689; c.-153 + 432A>C). The C allele segregated through unaffected individuals, found one other family. Functional assays showed that creates an allele-specific protein-binding site decreases promoter activity. We also observed loss gain fzd6 zebrafish contributes to craniofacial anomalies. regulates WNT signaling pathway, which involved development, including midfacial formation upper labial fusion. hypothesize, therefore, alteration expression by perturbing pathway.