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Frequency and distribution of polyQ disease intermediate-length repeat alleles in healthy Italian population

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Abstract

Background

Huntington disease (HD) and spinocerebellar ataxia type 1-2-17 (SCA1-2-17) are adult-onset autosomal dominant diseases, caused by triplet repeat expansions in the HTT, ATXN1, ATXN2, and TBP genes. Alleles with a repeat number just below the pathological threshold are associated with reduced penetrance and meiotic instability and are defined as intermediate alleles (IAs).

Objectives

We aimed to determine the frequencies of IAs in healthy Italian subjects and to compare the proportion of the IAs with the prevalence of the respective diseases.

Methods

We analyzed the triplet repeat size in HTT, ATXN1, ATXN2, and TBP genes in the DNA samples from 729 consecutive adult healthy Italian subjects.

Results

IAs associated with reduced penetrance were found in ATXN2 gene (1 subject, 0.1%) and TBP gene (0.82%). IAs at risk for meiotic instability were found in HTT (5.3%) and ATXN2 genes (2.7%). In ATXN1, we found a low percentage of IAs (0.4%). Alleles lacking the common CAT interruption within the CAG sequence were also rare (0.3%).

Conclusions

The high frequencies of IAs in HTT and ATXN2 genes suggest a correlation with the prevalence of the diseases in our population and support the hypothesis that IAs could represent a reservoir of new pathological expansions. On the opposite, ATXN1-IA were very rare in respect to the prevalence of SCA1 in our country, and TBP- IA were more frequent than expected, suggesting that other mechanisms could influence the occurrence of novel pathological expansions.

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Acknowledgments

The authors gratefully acknowledge all the subjects participating in the study.

Funding

The study was supported by the Italian Ministry of Health (Grant GR-2013-02357821 to LN).

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Author notes

  1. Alessia Mongelli and Stefania Magri contributed equally to this work.

Authors and Affiliations

  1. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

    Alessia Mongelli, Stefania Magri, Elena Rizzo, Marta Gatti, Cinzia Gellera, Franco Taroni, Caterina Mariotti & Lorenzo Nanetti

  2. Department of Neurosciences and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy

    Elena Salvatore, Anna De Rosa & Tommasina Fico

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  1. Alessia Mongelli
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  2. Stefania Magri
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Correspondence to Caterina Mariotti.

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All procedures performed in studies involving human participants have been approved by the institutional ethics committees and were in accordance with the ethical standards of the Fondazione IRCCS Istituto Neurologico Carlo Besta committee and of the “Federico II” University committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Fig. 1

Demographic data of participants enrolled for the study. In Panel A, age and sex distribution and in panel B the self-reported clinical history of individuals (PDF 261 kb)

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Mongelli, A., Magri, S., Salvatore, E. et al. Frequency and distribution of polyQ disease intermediate-length repeat alleles in healthy Italian population. Neurol Sci 41, 1475–1482 (2020). https://doi.org/10.1007/s10072-019-04233-3

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