Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by developmental arrest in the sensory and autonomic nervous systems and b y Ashkenazi Jewish ancestry. We previously had mapped the defective gene (D YS) to an 11-cM segment of chromosome 9q31-33, flanked by D9S53 and D9S105. By using 11 new polymorphic loci, we now have narrowed the location of DYS to <0.5 cM between the markers 43B1GAGT and 157A3. Two markers in this int erval, 164D1 and D9S1677, show no recombination with the disease. Haplotype analysis confirmed this candidate region and revealed a major haplotype sh ared by 435 of 441 FD chromosomes, indicating a striking founder effect. Th ree other haplotypes, found on the remaining 6 FD chromosomes, might repres ent independent mutations. The frequency of the major FD haplotype in the A shkenazim (5 in 324 control chromosomes) was consistent with the estimated DYS carrier frequency of 1 in 32, and none of the four haplotypes associate d with FD was observed on 492 non-FD chromosomes from obligatory carriers. It is now possible to provide accurate genetic testing both for families wi th FD and for carriers, on the basis of close flanking markers and the capa city to identify >98% of FD chromosomes by their haplotype.