Orofacial Cleft 13

For a phenotypic description and a discussion of genetic heterogeneity of nonsyndromic CL/P, see OFC1 (119530).

See also van der Woude syndrome-2 (VWS2; 606713), which maps to chromosome 1p34.

Cytogenetics

Ghassibe-Sabbagh et al. (2011) studied a family with Pierre-Robin syndrome, characterized by the triad of cleft palate only, micrognathia, and glossoptosis (see 261800), in which the affected father and son had the karyotype 46,XY,t(1;2)(p34;q33). The 1p breakpoint was found to interrupt the FAF1 gene (604460) within its first intron and FAF1 expression was decreased in the proband's lymphocytes compared to controls; analysis of the 2q breakpoint showed that the region was unlikely to play a role in the phenotype.

Rainger et al. (2014) reevaluated the father and son reported by Ghassibe-Sabbagh et al. (2011). Rainger et al. (2014) found that the 2q33 breakpoint in this family was about 896-kb centromeric to the SATB2 gene (608148) and likely interrupted SATB2 cis-regulatory elements. Rainger et al. (2014) suggested that the phenotype in these patients was consistent with Glass syndrome (612313), which is caused by functional haploinsufficiency of the SATB2 gene.

Mapping

Ghassibe-Sabbagh et al. (2011) genotyped 10 FAF1-associated SNPs on chromosome 1p33 in a cohort of 2,530 trios involving a patient with nonsyndromic cleft and that patient's parents. In 474 trios with isolated cleft palate only (CPO), the T allele of the SNP rs3827730 was significantly overtransmitted from heterozygous parents to affected children (p = 0.0003). The TT genotype of rs3827730 in a child was associated with an overall 1.47-fold increased risk of CPO.

Molecular Genetics

Ghassibe-Sabbagh et al. (2011) screened the FAF1 gene in a cohort of 228 individuals with clefts, including 14 patients with van der Woude syndrome (119300) in whom mutation in the IRF6 gene (607199) had been excluded, 34 patients with Pierre Robin syndrome, 65 patients with CPO, and 115 with CL/P, but did not find any changes significantly associated with clefts. In addition, analysis of SNPs did not reveal any copy number variation at 1p34 in 140 cleft patients. However, using quantitative RT-PCR on peripheral blood lymphocytes from 9 cleft patients and 2 controls, Ghassibe-Sabbagh et al. (2011) found a significant decrease in FAF1 expression in CPO and CL/P patients (p = 0.0015 and p = 0.01, respectively) compared to controls. Genotyping the patients for rs3827730 revealed an enrichment of the T allele (75% of alleles in CPO patients and 60% of alleles in CL/P patients).