Chromosomal duplication involving the forkhead transcription factor gene FOXC1 causes iris hypoplasia and glaucoma

The forkhead transcription factor gene FOXC1 (formerly FKHL7) is responsibl e for a number of glaucoma phenotypes in families in which the disease maps to 6p25, although mutations have not been found in all families in which t he disease maps to this region. In a large pedigree with iris hypoplasia an d glaucoma mapping to 6p25 (peak LOD score 6.20 [recombination fraction 0] at DGS967), no FOXC1 mutations were detected by direct sequencing. However, genotyping with microsatellite repeat markers suggested the presence of a chromosomal duplication that segregated with the disease phenotype. The dup lication was confirmed in affected individuals by FISH with markers encompa ssing FOXC1. These results provide evidence of gene duplication causing dev elopmental disease in humans, with increased gene dosage of either FOXC1 or other, as yet unknown genes within the duplicated segment being the probab le mechanism responsible for the phenotype.