Variation in WNT genes is associated with non-syndromic cleft lip with or without cleft palate

Abstract

Non-syndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect. Genetic and environmental factors have been causally implicated and studies have begun to delineate genetic contributions. The Wnt genes are involved in regulating mid-face development and upper lip fusion and are therefore strong candidates for an etiological role in NSCLP. Furthermore, the clf1 region in A/WyN clefting susceptible mice contains the Wnt3 and Wnt9B genes. To assess the role of the Wnt family of genes in NSCLP, we interrogated seven Wnt genes (Wnt3, Wnt3A, Wnt5A, Wnt7A, Wnt8A, Wnt9B and Wnt11) in our well-defined NSCLP dataset. Thirty-eight single nucleotide polymorphisms were genotyped in 132 multiplex NSCLP families and 354 simplex parent-child trios. In the entire dataset, single-nucleotide polymorphisms (SNPs) in three genes, Wnt3A (P = 0.006), Wnt 5A (P = 0.002) and Wnt11 (P = 0.0001) were significantly associated with NSCLP after correction for multiple testing. When stratified by ethnicity, the strongest associations were found for SNPs in Wnt3A (P = 0.0007), Wnt11 (P = 0.0012) and Wnt8A (P = 0.0013). Multiple haplotypes in Wnt genes were associated with NSCLP, and gene-gene interactions were observed between Wnt3A and both Wnt3 and Wnt5A (P = 0.004 and P = 0.039, respectively). This data suggests that alteration in Wnt gene function may perturb formation and/or fusion of the facial processes and predispose to NSCLP.

Variations in WNT3 gene are associated with incidence of non-syndromic cleft lip with or without cleft palate in a northeast Chinese population

“…Our results continued to support the theory that the WNT3 genes may be associated with the occurrence of NSCL/P. This report details supplemental research of a previous study (Chiquet et al, 2008), and may be helpful in extending our understanding of the etiology of NSCL/P.…”

“…A previous study reported that among the 13 SNPs investigated in the WNT3A, WNT5A, WNT8A, WNT11, WNT3, and WNT9B genes (in 463 Caucasian individuals), the rs142167 [P = 2.80E-05; OR = 1.61 (1.29-2.02)] and rs9890413 [P = 0.002; OR = 1.4 (1.12-1.74)] SNPs in WNT3 were significantly associated with all clefts (Menezes et al, 2010). Chiquet et al (2008) also discovered significant differences between the phenotypes of the rs9890413 SNP in the WNT3 gene in the European, American, and Hispanic population. These results indicate that the WNT3 gene is associated with NSCL/P.…”

Distinct requirements for wnt9a and irf6 in extension and integration mechanisms during zebrafish palate morphogenesis

“…In the mouse, Wnt9b is involved in fusion of the medial and lateral nasal processes (Juriloff et al, 2006;Lan et al, 2006;Ferretti et al, 2011). Variation of Wnt genes is associated with non-syndromic cleft lip and/or palate (CLP) in human and mouse studies (Juriloff et al, 2006;Chiquet et al, 2008). Knockdown of zebrafish wnt9a results in an abridged palate, where the bilateral trabeculae are joined in the midline but the ethmoid plate does not extend (Curtin et al, 2010).…”

Identification of the Differentially Expressed microRNAs Involved in Cleft Palate Induced by Retinoic Acid (RA) in Mouse Model

“…It has been demonstrated that WNT genes are associated with cleft lip and palate. Wnt3a, Wnt5a and Wnt11 are differentially expressed in non-syndromic cleft lip with or without cleft palate significantly 30) .…”