Oculodentodigital syndrome (OD) is a rare autosomal dominantly inherited syndrome characterized by developmental and morphogenic abnormalities (e.g. syndactyly, craniofacial anomalies, dental enamel hypoplasia, etc.), glaucoma, and a slowly progressive spastic paraparesis. We have utilized the resources of the GCRC to recruit multiple large families with OD and to perform linkage analysis to map the gene(s) for the disorder. To date we have ascertained 6 large families from the United States, Canada, and Norway comprising a total of 47 potentially genetically informative meioses (27 individuals affected with OD and 20 unaffected). I have performed physical examinations on >85% of these individuals to confirm their phenotype. One observation which emerged from these analyses is that the severity of the dysmorphic traits and/or the age of onset of the spastic paraparesis appear to follow the pattern of trait expression known as genetic anticipation, that is, greater phenotypic severity and/or an earlier age of onset of inherited traits may occur in successive generations. Comparable to known genes for several other diseases with anticipation, this phenotypic inheritance pattern suggests the presence of a trinucleotide repeat expansion in the gene responsible for the disease. A paper reporting these observations is in press in the American Journal of Medical Genetics. Using these kindreds, we have embarked on a genome-wide search for linkage of short tandem repeat polymorphic (STRP) markers to the OD disease phenotype. In our initial results, genomic regions of chromosomes 2, 7, 12, and 17 containing HOX gene clusters were excluded as candidate loci for OD for all kindreds. Last month, a paper reported localization of a gene for OD to chromosome 6q22-q24 (Hum Mol Genet 6:123 (97)). We have recently obtained genotypes for markers in this interval for our kindreds. We have confirmed linkage of OD to this locus in an analysis which combines our kindreds, and we have significantly further refined the chromosomal interval in which a suceptibility gene must lie. We are currently characterizing more polymorphic marker genotypes to narrow this interval further, in the genetic material we have collected as well as in new OD families recruited to the study. Simultaneously, we are testing genes in the 6q22-q24 region for expanded triplet repeats as candidates for the genetic mutation underlying OD.
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