Van Der Woude Syndrome 2

A number sign (#) is used with this entry because of evidence that van der Woude syndrome-2 (VWS2) is caused by heterozygous mutation in the GRHL3 gene (608317) on chromosome 1p36.

Description

Van der Woude syndrome (VWS) is a dominantly inherited developmental disorder characterized by pits and/or sinuses of the lower lip, and cleft lip and/or cleft palate (CL/P, CP). It is the most common cleft syndrome.

For a discussion of genetic heterogeneity of van der Woude syndrome, see VWS1 (119300).

Clinical Features

Koillinen et al. (2001) studied a large Finnish pedigree with van der Woude syndrome in which the clinical features were typical for VWS with the exception that usually CL/P is twice as common as CP, but in this family, 9 of the 11 affected individuals had CP and only 1 had CL/P. In addition, only 1 affected family member exhibited lip pits, and he did not have clefting anomalies. Noting that lip pits are present in 80% of VWS patients, Koillinen et al. (2001) suggested that this family might represent a new subtype or variation of VWS.

Mapping

Although VWS had shown remarkable genetic homogeneity in all populations, with most reported families showing linkage to chromosome 1q32-q41 (see 119300) due to mutation in the IRF6 gene (607199), Koillinen et al. (2001) mapped a second locus for VWS (VWS2) to chromosome 1p34 by a genomewide linkage scan in a large Finnish pedigree that did not show linkage to the chromosome 1q32-q41 region. A maximum lod score of 3.18 was obtained at marker D1S2797 (theta = 0.0), and analysis of meiotic recombinants demonstrated a 30-cM region of shared haplotype. The transmission pattern was consistent with autosomal dominant inheritance.

Inheritance

The transmission pattern of VWS in the family reported by Koillinen et al. (2001) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 8 affected and 3 unaffected members of the large Finnish VWS pedigree reported by Koillinen et al. (2001), Peyrard-Janvid et al. (2014) performed targeted exome sequencing and identified a heterozygous 2-bp insertion in the GRHL3 gene (608317.0001) that segregated with disease in the family and was not found in 561 Finnish controls. Screening of 44 additional VWS families who were known to be negative for causative mutations in the IRF6 gene (607199) revealed heterozygous GRHL3 mutations in 6 (see, e.g., 608317.0002-608317.0005), including 1 family previously reported by Peyrard-Janvid et al. (2005) and 1 previously reported by Malik et al. (2010). In 1 proband, 2 GRHL3 variants were found to be located in trans: a frameshift mutation inherited from her affected father and healthy paternal grandfather, and a missense mutation inherited from her healthy mother. Peyrard-Janvid et al. (2014) noted that 1 proband (see 608317.0003) had previously been found to carry an IRF6 missense variant (K80R) that was not conclusively determined to be causative (Malik et al., 2010), raising the possibility that variants in both IRF6 and GRHL3 could contribute to VWS in 1 family.

Leslie et al. (2016) performed genomewide analysis of nonsyndromic cleft palate (CP) and found significant association with a missense variant in GRHL3 (T454M, rs41268753; p = 4.08 X 10(-9)) and replicated the result in an independent cohort. The authors noted that the minor allele frequency of rs41268753 among European controls was 2.75%, consistent with the 3.06% frequency reported in non-Finnish European populations in the ExAC database. However, the elevated frequency of the T454M variant in both the discovery and replication samples conferred increased risk for CP (odds ratios of 8.3 and 2.16, respectively). The mutant showed activity of about one-third of wildtype in luciferase transactivation assays and perturbed periderm development in zebrafish embryos. Leslie et al. (2016) concluded that the T454M variant is an etiologic variant for nonsyndromic CP.

Mangold et al. (2016) performed genomewide analysis of nonsyndromic cleft lip/palate (CLP) and CP only (CPO) and found significant association with the T454M variant in GRHL3, but only for nonsyndromic CPO (p combined = 2.73 X 10(-9)). Sequencing GRHL3 in 672 Central European individuals with nonsyndromic clefting identified 4 CPO probands with truncating mutations not found in the Exome Variant Server, 1000 Genomes Project, ExAC, or GoNL databases. The mutations, 3 splice site and 1 frameshift, segregated with cleft palate in the respective families. None of the 9 affected individuals showed the typical lip pits seen in VWS. However, in 1 family in which the affected mother exhibited a broad uvula and nasal speech that was 'strongly suggestive' of submucous cleft palate, close examination of 2 daughters who had clefting of the hard and soft palates revealed irregularities of the lower lip that might represent subtle lip pits. The authors designated this to be a 'transitional' phenotype, and suggested that it was likely that in the other families some descendants would have lip pits and/or CLP. In contrast to VWS-associated mutations, the mutations associated with nonsyndromic clefting were all located within the GRHL3 DNA-binding domain; Mangold et al. (2016) stated that further investigation would be required to determine whether this reflected a genuine genotype-phenotype correlation.

Genotype/Phenotype Correlations

Peyrard-Janvid et al. (2014) tested for phenotypic variation between the VWS1 and VWS2 loci and found that individuals with a GRHL3 mutation were significantly more likely to have CP and less likely to have CL/P than individuals with IRF6 mutations. Lip pits were less frequent among individuals with GRHL3 mutations, but the difference was not statistically significant, and the presence of dental and limb anomalies did not differ significantly between the 2 groups.

Animal Model

Peyrard-Janvid et al. (2014) assayed the effect of GRHL3 mutations on Grhl3 function in zebrafish and observed abrogation of periderm development, consistent with a dominant-negative effect. In mouse, all 6 embryos lacking Grhl3 exhibited abnormal oral periderm and 1 (17%) developed cleft palate. Analysis of the oral phenotype of double-heterozygote (Irf6 +/-; Grhl3 +/-) murine embryos failed to demonstrate epistasis between the 2 genes, suggesting that they function in separate but convergent pathways during palatogenesis.

History

In the Finnish pedigree with van der Woude syndrome mapping to chromosome 1p34, Rorick et al. (2011) analyzed 2 candidate genes that fulfilled criteria for regulation by the IRF6 (607199) gene, SFN (601290) and WDR65 (614259), but did not find any etiologic mutation. Analysis of SFN and WDR65 in 48 individuals with VWS who were known to be negative for mutation in IRF6 revealed a missense mutation in WDR65 (D5232Y; 614259.0001) in a Brazilian patient that was not found in controls. Noting that the mutation significantly changes the biochemical properties of a conserved residue, Rorick et al. (2011) concluded that it was potentially etiologic. In the Finnish pedigree studied by Koillinen et al. (2001) and Rorick et al. (2011), and in 7 additional VWS pedigrees without mutation in IRF6, Peyrard-Janvid et al. (2014) found heterozygous mutation in the GRHL3 gene on chromosome 1p36 segregating with the disorder.