Abstract

Foramina parietalia permagna (FPP) (OMIM 168500) is caused by ossification defects in the parietal bones. Recently, it was shown that loss of function mutations in the MSX2homeobox gene on chromosome 5 are responsible for the presence of these lesions in some FPP patients. However, the absence ofMSX2 mutations in some of the FPP patients analysed and the presence of FPP associated with chromosome 11p deletions in DEFECT 11 (OMIM 601224) patients or associated with Saethre-Chotzen syndrome suggests genetic heterogeneity for this disorder. Starting from a BAC/P1/cosmid contig of the DEFECT 11 region on chromosome 11, we have now isolated theALX4 gene, a previously unidentified member of the ALX homeobox gene family in humans. Mutation analysis of the ALX4 gene in three unrelated FPP families without the MSX2mutation identified mutations in two families, indicating that mutations in ALX4 could be responsible for these skull defects and suggesting further genetic heterogeneity of FPP.