G08 An italian study to estimate the frequency of the intermediate triplet length in the huntingtin gene: 1/20 subject carries an allele with 27–35 cag

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Abstract

Background

Huntington disease (HD) is an autosomal dominant disorder caused by CAG repeat expansions in the huntingtin gene (≥40). Alleles with repeat number slightly below the pathological threshold are defined as intermediate (IAs), and are associated with reduced penetrance (36–39 CAG) and meiotic instability (27–35 CAG). Previous studies demonstrated an elevated allelic frequency of HD-IA in healthy subjects (2.9%).

Aims

To investigate the frequency of HD-IA in the healthy Italian population.

Methods

459 adult healthy Italian subjects (177 M/189 F) were enrolled at Milan and Naples Neurological Centers. Participants were partners or caregivers of patients referred to the clinical Centers. Demographic and anamnestic data were collected. As comparison we also investigate the allelic frequencies of IAs in SCA1-2-17 genes.

Results

Subjects had a mean age of 56.3±11.9 years (range 19–84). Most relevant comorbidities were arterial hypertension (30% of subjects), hypercholesterolemia (30%) and diabetes (6%). Twenty-four subjects were found to carry an HD-IA (5.2%), indicating an allelic frequency of 2.6%. Nineteen subjects carried 27–29 CAG, and 5 carried 30–35 CAG. IAs in SCA1-2-17 genes ranged form 0.1 to 0.3%.

Conclusions

The participants were representative of the Italian population in terms of sex, age and comorbidities. In accordance with previous studies, we confirmed a high frequency of HD-IA also in Italy. IAs for other polyglutamine disorders were very rare. HD-IA could represent a reservoir for fully pathological expanded alleles in the future generations and impact the incidence of HD disease and genetic counseling. Neuroradiological and cognitive evaluations in the 30–35 IAs carriers are ongoing.

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