Huntington's disease in French families: CAG repeat expansion and linkage disequilibrium analysis.

The molecular defect causing Huntington's disease (HD) has been found as an expansion of CAG triplets in the 5' coding region of IT15 gene. In the 29 French families reported, the HD disease is due to the expansion of the CAG triplets region above 38 copies. The complete sequencing of 10 HD alleles PCR products allowed us to confirm that expansion is restricted to the CAG repeat region and does not extend to the adjacent CCG repeat region which is also present in the PCR product. Then, we analysed linkage disequilibrium between the molecular defect and 6 DNA markers mapping to the 4p16.3 region. The most striking finding in this study is the presence of a strong linkage disequilibrium between HD and D4S127 (PvuII), D4S95 (AccI, MboI, TaqI) located in a region of 130 kb distal to IT15 gene. Two major haplotypes, comprising D4S127 (PvuII) and D4S95 (MboI, AccI) polymorphic sites, were found in the normal population as only one was found associated with HD alleles. This result can be interpreted either as an evidence for a rather recent founder effect or as several independent mutations occuring in chromosomes bearing the same haplotype.