A COMMON DLX3 GENE MUTATION IS RESPONSIBLE FOR TRICHODENTOOSSEOUS SYNDROME IN VIRGINIA AND NORTH-CAROLINA FAMILIES

Tricho-dento-osseous syndrome (TDO) is characterised by a variable cli nical phenotype primarily affecting the hair, teeth, and bone. Differe nt clinical features are observed between and within TDO families. It is not known whether the variable clinical features are the result of genetic heterogeneity or clinical variability. A gene for TDO was loca lised recently to chromosome 17q21 in four North Carolina families, an d a 4 bp deletion in the human distal-less 3 gene (DLX3) was identifie d in all affected members. A previous genetic linkage study in a large Virginia kindred with TDO indicated possible linkage to the ABO, Cc, and Kell blood group loci. To examine whether TDO exhibits genetic het erogeneity, we have performed molecular genetic analysis to determine whether affected members of this Virginia kindred have the DLX3 gene d eletion identified in North Carolina families. Results show that affec ted subjects (n=3) from the Virginia family have the same four nucleot ide deletion previously identified in the North Carolina families. A c ommon haplotype for three genetic markers surrounding the DLX3 gene wa s identified in all affected subjects in the North Carolina and Virgin ia families. These findings suggest that all people with TDO who have been evaluated have inherited the same DLX3 gene deletion mutation fro m a common ancestor. The variable clinical phenotype observed in these North Carolina and Virginia families, which share a common gene mutat ion, suggests that clinical variability is not the result of genetic h eterogeneity at the major locus, but may reflect genetic heterogeneity at other epigenetic loci or contributing environmental factors or bot h.