Bloom syndrome and Fanconi's anemia: rate and ethnic origin of mutation carriers in Israel.

Background: The Bloom syndrome gene, BLM, was mapped to 15q26.1 and its product was found to encode a RecQ DNA helicase. The Fanconi's anemia complementation group C gene was mapped to chromosome 9q22.3, but its product function is not sufficiently clear. Both are recessive disorders associated with an elevated predisposition to cancer due to genomic instability. A single predominant mutation of each disorder was reported in Ashkenazi Jews: 2281delATCTGAinsTAGATTC for Bloom syndrome (BLM-ASH) and IVS4 + 4AT for Fanconi's anemia complementation group C.
Objectives: To provide additional verification of the mutation rate of BLM and FACC in unselected Ashkenazi and non-Ashkenazi populations analyzed at the Sheba Medical Center, and to trace the origin of each mutation.
Methods: We used polymerase chain reaction to identify mutations of the relevant genomic fragments, restriction analysis and gel electrophoresis. We then applied the Pronto kit to verify the results in 244 samples and there was an excellent match.
Results: A heterozygote frequency of 1:111 for BLM-ASH and 1:92 for FACC was detected in more than 4,000 participants, none of whom reported a family history of the disorders. The Pronto kit confirmed all heterozygotes. Neither of the mutations was detected in 950 anonymous non-Ashkenazi Jews. The distribution pattern of parental origin differed significantly between the two carrier groups, as well as between each one and the general population.
Conclusions: These findings as well as the absence of the mutations in non-Ashkenazi Jews suggest that: a) the mutations originated in the Israelite population that was exiled from Palestine by the Roman Empire in 70 AD and settled in Europe (Ashkenazi), in contrast to those who remained; and b) the difference in origin distribution of the BS and FACC mutations can be explained by either a secondary migration of a subgroup with a subsequent genetic drift, or a separate geographic region of introduction for each mutation.