Specific mutations in the HEXA gene among Iraqi Jewish Tay-Sachs disease carriers: Dating of founder ancestor

The incidence of Tay-Sachs disease (TSD) carriers, as defined by enzyme assay, is 1:29 among Ashkenazi Jews and 1:110 among Moroccan Jews. An elevated carrier frequency of 1:140 was also observed in the Iraqi Jews (IJ), while in other Israeli populations the world's pan-ethnic frequency of approximately 1:280 has been found. Recently a novel mutation, G⁷⁴⁹T, has been reported in 38.7% of the IJ carriers (24/62). Here we report a second novel HEXA mutation specific to the IJ TDS carriers: a substitution of cytosine 1351 by guanosine (C¹³⁵¹G), resulting in the change of leucine to valine in position 451. This mutation was found in 33.9% (21/62) of the carriers and in none of 100 non-carrier IJ. In addition to the two specific mutations, 14.5% (9/62) of the IJ carriers bear a known "Jewish" mutation (Ashkenazi or Moroccan) and 11.3% (7/62) carry a known "non-Jewish" mutation. In 1 DNA sample no mutation has yet been detected. To investigate the genetic history of the IJ-specific mutations (C¹³⁵¹G and G⁷⁴⁹T), the allelic distribution of four polymorphic markers (D15S131, D15S1025, D15S981, D15S1050) was analyzed in IJ heterozygotes and ethnically matched controls. Based on linkage disequilibrium, recombination factor (0) between the markers and mutated loci, and the population growth correction, we deduced that G⁷⁴⁹T occurred in a founder ancestor 44.8±14.2 generations (g) ago [95% confidence interval (CI) 17.0-72.6 g] and C¹³⁵¹G arose 80.4±35.9 g ago (95% CI 44.5-116.3 g). Thus, the estimated dates for introduction of mutations are: 626±426 A.D. (200-1052 A.D.) for G ⁷⁴⁹T and 442±1077 B.C. (1519 B.C. to 635 A.D.) for C ¹³⁵¹G.