Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome

Heterozygous mutations in MSX2 are responsible for an autosomal dominant fo rm of parietal foramina (PFM). PFM are oval defects of the parietal bones t hat are also a characteristic feature of a contiguous gene-deletion syndrom e caused by a proximal deletion in the short arm of chromosome 11 (Potocki- Shaffer syndrome). We have identified a human bacterial artificial chromoso me (BAC) clone mapping to chromosome 11, containing a region homologous to the human homeobox gene MSX2. Further sequence analysis demonstrated that t he human orthologue (ALX4) of the mouse Aristaless-like 4 gene (Alx4) is co ntained within this 11p clone. We used FISH to test for the presence-or for the heterozygous deletion-of this clone in two patients with the 11p11.2-d eletion syndrome and showed that this clone is deleted in these patients. A LX4 and Alx4 were shown to be expressed in bone and to be absent from all o ther tissues tested. The involvement of Alx4 in murine skull development, i ts bone-specific expression pattern, the fact that Alx4 is a dosage-sensiti ve gene in mice, and the localization of a human genomic clone containing A LX4 to 11p11.2, with hemizygosity in patients with deletion of 11p11.2 who have biparietal foramina, support the contention that ALX4 is a candidate g ene for the PFM in the 11p11.2-deletion syndrome.