Abstract for presentation at 11th International Congress of Human Genetics

Huntington disease (HD) is a progressive neurodegenerative disorder that results from expansion of a polymorphic trinucleotide (CAG) tract in the HD gene. The average CAG tract size in the general population is 17-20 repeats, however, in HD patients, the CAG tract has expanded beyond 36 repeats. The origins of the HD mutation and the genetic factors that contribute to new occurrences of the HD mutation have not been fully described. We genotyped 24 tag SNPs derived from the Haplotype Map in the HD gene using the SNPStream genotyping platform on more than 300 HD families. After phasing the haplotypes and performing a phylogenetic analysis with the MEGA software, we show that more than 90% of HD chromosomes share a common haplotype background. Also, de novo cases in families with no previous history of HD are associated with these haplotypes with a similar frequency. Moreover these haplotypes are associated with a higher number of repeats in the general population (> 20 on average) and instability of the transmitted number of repeats. These haplotypes are relatively common in the general European population (about 20%), but are practically absent in China, Japan and in individuals of Yoruba origin reflecting the fact that the prevalence of HD is much lower in these populations. These results suggest that events triggered an expansion of the repeat size at the time or just before the colonisation of Europe. Whether these genetic events actively induce a mutator phenotype or are linked only to the CAG repeat size remains to be clarified.