A locus for isolated cleft palate, located on human chromosome 2q32

We present evidence for the existence of a novel chromosome 2q32 locus invo lved in the pathogenesis of isolated cleft palate. We have studied two unre lated patients with strikingly similar clinical features, in whom there are apparently balanced, de novo cytogenetic rearrangements involving the same region of chromosome 2q. Both children have cleft palate, facial dysmorphi sm, and mild learning disability. Their karyotypes were originally reported as 46, XX, t(2;7)(q33;p21) and 46, XX, t(2;11)(q33;p14). However, our mole cular cytogenetic analyses localize both translocation breakpoints to a sma ll region between markers D2S311 and D2S116. This suggests that the true lo cation of these breakpoints is 2q32 rather than 2q33. To obtain independent support for the existence of a cleft-palate locus in 2q32, we performed a detailed statistical analysis for all cases in the human cytogenetics datab ase of nonmosaic, single, contiguous autosomal deletions associated with or ofacial clefting. This revealed 2q32 to be one of only three chromosomal re gions in which haploinsufficiency is significantly associated with isolated cleft palate. In combination, our data provide strong evidence for the loc ation at 2q32 of a gene that is critical to the development of the secondar y palate. The close proximity of these two translocation breakpoints should also allow rapid progress toward the positional cloning of this cleft-pala te gene.