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Am J Hum Genet. 1992 Mar;50(3):619-28.

Strong allelic association between the torsion dystonia gene (DYT1) andloci on chromosome 9q34 in Ashkenazi Jews.

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Molecular Neurogenetics Unit, Massachusetts General Hospital East, Charlestown 02129.


The DYT1 gene responsible for early-onset, idiopathic torsion dystonia (ITD) in the Ashkenazi Jewish population, as well as in one large non-Jewish family, has been mapped to chromosome 9q32-34. Using (GT)n and RFLP markers in this region, we have identified obligate recombination events in some of these Jewish families, which further delineate the area containing the DYT1 gene to a 6-cM region bounded by loci AK1 and ASS. In 52 unrelated, affected Ashkenazi Jewish individuals, we have found highly significant linkage disequilibrium between a particular extended haplotype at the ABL-ASS loci and the DYT1 gene. The 4/A12 haplotype for ABL-ASS is present on 69% of the disease-bearing chromosomes among affected Jewish individuals and on only 1% of control Jewish chromosomes (chi 2 = 91.07, P much less than .001). The allelic association between this extended haplotype and DYT1 predicts that these three genes lie within 1-2 cM of each other; on the basis of obligate recombination events, the DYT1 gene is centromeric to ASS. Furthermore, this allelic association supports the idea that a single mutation event is responsible for most hereditary cases of dystonia in the Jewish population. Of the 53 definitely affected typed, 13 appear to be sporadic, with no family history of dystonia. However, the proportion of sporadic cases which potentially carry the A12 haplotype at ASS (8/13 [62%]) is similar to the proportion of familial cases with A12 (28/40 [70%]). This suggests that many sporadic cases are hereditary, that the disease gene frequency is greater than 1/15,000, and that the penetrance is lower than 30%, as previously estimated in this population. Most affected individuals were heterozygous for the ABL-ASS haplotype, a finding supporting autosomal dominant inheritance of the DYT1 gene. The ABL-ASS extended-haplotype status will provide predictive value for carrier status in Jewish individuals. This information can be used for molecular diagnosis, evaluation of subclinical expression of the disease, and elucidation of environmental factors which may modify clinical symptoms.

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