Physical and transcriptional mapping of the X-linked cleft palate and ankyloglossia (CPX) critical region

Cleft palate most commonly occurs as a sporadic multifactorial disorder with a clear but difficult to define genetic component. As a semi-dominant disorder, X-linked cleft palate (CPX) provides a useful model to investigate a congenital defect that is little influenced by non-genetic factors. By using an Icelandic kindred, CPX has been localised between DXS1196 and DXS1217 and mapped, in a 3-Mb yeast artificial chromosome contig, at Xq21.3. Markers generated from this physical map have now been used to construct a contig of PI and bacterial artificial chromosome clones for genomic DNA sequencing. Genomic DNA sequence analysis has revealed two novel expressed genes and two pseudogenes in the order Cen-KLHL4-LAMRL5-CAPZA1P-CPXCR1-Tel. KLHL4 and CPXCR1 are widely expressed in fetal tissues, including the tongue, mandible and palate. DNA mutation screening of CPXCR1 has revealed several sequence variants present on all affected CPX chromosomes. However, these variants have also been detected at a lower frequency on unaffected chromosomes, indicating that they are polymorphisms that are unlikely to cause the CPX phenotype.