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Genetic polymorphisms adjacent to the CAG repeat influence clinical features at onset in Huntington’s disease

OBJECTIVES To evaluate possible influences of CCG and Δ2642 glutamic acid polymorphisms adjacent to the (CAG)n trinucleotide repeat in Huntington’s disease gene IT15 on some clinical features (age and symptoms) at onset. METHODS 84 patients and a control group of 68 unaffected relatives were studied. Patients all belonged to a group of affected persons tested for molecular confirmation of Huntington’s disease. The length of the CAG repeat sequence in the IT15 gene and the adjacent CCG and Δ2642 polymorphisms were determined by quantitative polymerase chain reaction. RESULTS Two intragenic polymorphisms were studied: (CCG)n and Δ2642 glutamic acid. Patients were classified firstly according to the size of the CCG rich segment adjacent to the CAG repeat into genotype groups CCG 7/7, 7/8, 7/9, 7/10, and 10/10 and then according to Δ2642 polymorphism into genotype groups A/A (absence of the Δ2642 deletion), A/B, and B/B (presence of the Δ2642 deletion in respectively one and two alleles). The presence of Δ2642 mutation was associated with a significant decrease in age at onset, although there was no significant increase in CAG size. A good correlation was found between the (CAG)n trinucleotide repeat size and the age at onset in patients with genotype AA (r 2=0.72). Within patients of the A/B genotype group however, a significant correlation was found but with a drop of the r 2 value to 0.44. No association was found between age at onset and the CCG polymorphism. Although an increased percentage of patients within the A/A genotype group had a neurological onset, we found no overall significant association between CCG or Δ2642 polymorphisms and the nature of symptoms at onset. CONCLUSIONS The Δ2642 glutamic acid polymorphism did not affect CAG repeat size nor the nature of symptoms at onset but seems to influence the age at onset in patients with Huntington’s disease.