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

  • Alessia Mongelli
  • Stefania Magri
  • Elena Salvatore
  • Elena Rizzo
  • Anna De Rosa
  • Tommasina Fico
  • Marta Gatti
  • Cinzia Gellera
  • Franco Taroni
  • Caterina MariottiEmail author
  • Lorenzo Nanetti
Original Article



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).


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.


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


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%).


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.


Huntington disease Spinocerebellar ataxia Intermediate alleles 



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

Funding information

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

Compliance with ethical standards

Statement of ethics

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.

Disclosure statement

The authors have no conflicts of interest to declare.

Supplementary material

10072_2019_4233_MOESM1_ESM.pdf (261 kb)
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)


  1. 1.
    Orr HT, Zoghbi HY (2007) Trinucleotide repeat disorders. Annu Rev Neurosci 30:575–621. CrossRefGoogle Scholar
  2. 2.
    Gardiner SL, Boogaard MW, Trompet S, de Mutsert R, Rosendaal FR, Gussekloo J, Jukema JW, Roos RAC, Aziz NA (2019) Prevalence of carriers of intermediate and pathological Polyglutamine disease-associated alleles among large population-based cohorts. JAMA Neurol. CrossRefGoogle Scholar
  3. 3.
    Semaka A, Kay C, Doty CN, Collins JA, Tam N, Hayden MR (2013) High frequency of intermediate alleles on Huntington disease-associated haplotypes in British Columbia's general population. Am J Med Genet B Neuropsychiatr Genet 162B:864–871. CrossRefGoogle Scholar
  4. 4.
    Kay C, Collins JA, Wright GEB, Baine F, Miedzybrodzka Z, Aminkeng F, Semaka AJ, McDonald C, Davidson M, Madore SJ, Gordon ES, Gerry NP, Cornejo-Olivas M, Squitieri F, Tishkoff S, Greenberg JL, Krause A, Hayden MR (2018) The molecular epidemiology of Huntington disease is related to intermediate allele frequency and haplotype in the general population. Am J Med Genet B Neuropsychiatr Genet 177:346–357. CrossRefGoogle Scholar
  5. 5.
    Rawlins MD, Wexler NS, Wexler AR, Tabrizi SJ, Douglas I, Evans SJ, Smeeth L (2016) The prevalence of Huntington's disease. Neuroepidemiology 46:144–153. CrossRefGoogle Scholar
  6. 6.
    Ruano L, Melo C, Silva MC, Coutinho P (2014) The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology 42:174–183. CrossRefGoogle Scholar
  7. 7.
    Zortea M, Armani M, Pastorello E, Nunez GF, Lombardi S, Tonello S, Rigoni MT, Zuliani L, Mostacciuolo ML, Gellera C, Di Donato S, Trevisan CP (2004) Prevalence of inherited ataxias in the province of Padua, Italy. Neuroepidemiology 23:275–280. CrossRefGoogle Scholar
  8. 8.
    Brusco A, Gellera C, Cagnoli C, Saluto A, Castucci A, Michielotto C, Fetoni V, Mariotti C, Migone N, Di Donato S, Taroni F (2004) Molecular genetics of hereditary spinocerebellar ataxia: mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families. Arch Neurol 61:727–733. CrossRefGoogle Scholar
  9. 9.
    Mariotti C, Alpini D, Fancellu R, Soliveri P, Grisoli M, Ravaglia S, Lovati C, Fetoni V, Giaccone G, Castucci A, Taroni F, Gellera C, Di Donato S (2007) Spinocerebellar ataxia type 17 (SCA17): oculomotor phenotype and clinical characterization of 15 Italian patients. J Neurol 254:1538–1546. CrossRefGoogle Scholar
  10. 10.
    Mongelli A, Sarro L, Rizzo E, Nanetti L, Meucci N, Pezzoli G, Goldwurm S, Taroni F, Mariotti C, Gellera C (2018) Multiple system atrophy and CAG repeat length: a genetic screening of polyglutamine disease genes in Italian patients. Neurosci Lett 678:37–42. CrossRefGoogle Scholar
  11. 11.
    Zühlke C, Dalski A, Hellenbroich Y, Bubel S, Schwinger E, Bürk K (2002) Spinocerebellar ataxia type 1 (SCA1): phenotype-genotype correlation studies in intermediate alleles. Eur J Hum Genet 10:204–209. CrossRefGoogle Scholar
  12. 12.
    Semaka A, Hayden MR (2014) Evidence-based genetic counselling implications for Huntington disease intermediate allele predictive test results. Clin Genet 85:303–311. CrossRefGoogle Scholar
  13. 13.
    Sequeiros J, Ramos EM, Cerqueira J, Costa MC, Sousa A, Pinto-Basto J, Alonso I (2010) Large normal and reduced penetrance alleles in Huntington disease: instability in families and frequency at the laboratory, at the clinic and in the population. Clin Genet 78:381–387. CrossRefGoogle Scholar
  14. 14.
    Semaka A, Collins JA, Hayden MR (2010) Unstable familial transmission of Huntigton disease alleles with 27-35 CAG repeats (intermediate alleles). Am J Med Genet B Neuropsychiatr Genet 153(B):314–320. CrossRefGoogle Scholar
  15. 15.
    Pulkes T, Papsing C, Wattanapokayakit S, Mahasirimongkol S (2014) CAG-expansion haplotype analysis in a population with a low prevalence of Huntington's disease. J Clin Neurol 10:32–36. CrossRefGoogle Scholar
  16. 16.
    Velázquez Pérez L, Cruz GS, Santos Falcón N, Enrique Almaguer Mederos L, Escalona Batallan K, Rodríguez Labrada R, Paneque Herrera M, Laffita Mesa JM, Rodríguez Díaz JC, Rodríguez RA, González Zaldivar Y, Coello Almarales D, Almaguer Gotay D, Jorge Cedeño H (2009) Molecular epidemiology of spinocerebellar ataxias in Cuba: insights into SCA2 founder effect in Holguin. Neurosci Lett 454:157–160. CrossRefGoogle Scholar
  17. 17.
    Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM, Padmanabhan A, Clay-Falcone D, McCluskey L, Elman L, Juhr D, Gruber PJ, Rüb U, Auburger G, Trojanowski JQ, Lee VM, Van Deerlin VM, Bonini NM, Gitler AD (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069–1075. CrossRefGoogle Scholar
  18. 18.
    Gispert S, Kurz A, Waibel S, Bauer P, Liepelt I, Geisen C, Gitler AD, Becker T, Weber M, Berg D, Andersen PM, Krüger R, Riess O, Ludolph AC, Auburger G (2012) The modulation of amyotrophic lateral sclerosis risk by ataxin-2 intermediate polyglutamine expansions is a specific effect. Neurobiol Dis 45:356–361. CrossRefGoogle Scholar
  19. 19.
    Lu HP, Gan SR, Chen S, Li HF, Liu ZJ, Ni W, Wang N, Wu ZY (2015) Intermediate-length polyglutamine in ATXN2 is a possible risk factor among eastern Chinese patients with amyotrophic lateral sclerosis. Neurobiol Aging 36:1603.e1611–1603.e1604. CrossRefGoogle Scholar
  20. 20.
    Socal MP, Emmel VE, Rieder CR, Hilbig A, Saraiva-Pereira ML, Jardim LB (2009) Intrafamilial variability of Parkinson phenotype in SCAs: novel cases due to SCA2 and SCA3 expansions. Parkinsonism Relat Disord 15:374–378. CrossRefGoogle Scholar
  21. 21.
    Lattante S, Pomponi MG, Conte A, Marangi G, Bisogni G, Patanella AK, Meleo E, Lunetta C, Riva N, Mosca L, Carrera P, Bee M, Zollino M, Sabatelli M (2018) ATXN1 intermediate-length polyglutamine expansions are associated with amyotrophic lateral sclerosis. Neurobiol Aging 64:157.e151–157.e155. CrossRefGoogle Scholar
  22. 22.
    Freund AA, Scola RH, Teive HA, Arndt RC, da Costa-Ribeiro MC, Alle LF, Werneck LC (2009) Spinocerebellar ataxias: microsatellite and allele frequency in unaffected and affected individuals. Arq Neuropsiquiatr 67:1124–1132CrossRefGoogle Scholar
  23. 23.
    Wu YR, Lin HY, Chen CM, Gwinn-Hardy K, Ro LS, Wang YC, Li SH, Hwang JC, Fang K, Hsieh-Li HM, Li ML, Tung LC, Su MT, Lu KT, Lee-Chen GJ (2004) Genetic testing in spinocerebellar ataxia in Taiwan: expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson's disease. Clin Genet 65:209–214. CrossRefGoogle Scholar
  24. 24.
    Goldfarb LG, Vasconcelos O, Platonov FA, Lunkes A, Kipnis V, Kononova S, Chabrashvili T, Vladimirtsev VA, Alexeev VP, Gajdusek DC (1996) Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1. Ann Neurol 39:500–506. CrossRefGoogle Scholar
  25. 25.
    Sobczak K, Krzyzosiak WJ (2004) Patterns of CAG repeat interruptions in SCA1 and SCA2 genes in relation to repeat instability. Hum Mutat 24:236–247. CrossRefGoogle Scholar
  26. 26.
    Nethisinghe S, Pigazzini ML, Pemble S, Sweeney MG, Labrum R, Manso K, Moore D, Warner J, Davis MB, Giunti P (2018) PolyQ tract toxicity in SCA1 is length dependent in the absence of CAG repeat interruption. Front Cell Neurosci 12:200.
  27. 27.
    Menon RP, Nethisinghe S, Faggiano S, Vannocci T, Rezaei H, Pemble S, Sweeney MG, Wood NW, Davis MB, Pastore A, Giunti P (2013) The role of interruptions in polyQ in the pathology of SCA1. PLoS Genet 9:e1003648. CrossRefGoogle Scholar
  28. 28.
    Chung MY, Ranum LP, Duvick LA, Servadio A, Zoghbi HY, Orr HT (1993) Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I. Nat Genet 5:254–258. CrossRefGoogle Scholar
  29. 29.
    Choudhry S, Mukerji M, Srivastava AK, Jain S, Brahmachari SK (2001) CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms. Hum Mol Genet 10(21):2437–2446. CrossRefGoogle Scholar
  30. 30.
    Hire RR, Katrak SM, Vaidya S, Radhakrishnan K, Seshadri M (2011) Spinocerebellar ataxia type 17 in Indian patients: two rare cases of homozygous expansions. Clin Genet 80:472–477. CrossRefGoogle Scholar
  31. 31.
    Zühlke C, Dalski A, Schwinger E, Finckh U (2005) Spinocerebellar ataxia type 17: report of a family with reduced penetrance of an unstable Gln49 TBP allele, haplotype analysis supporting a founder effect for unstable alleles and comparative analysis of SCA17 genotypes. BMC Med Genet 6:27.
  32. 32.
    Nethisinghe S, Lim WN, Ging H, Zeitlberger A, Abeti R, Pemble S, Sweeney MG, Labrum R, Cervera C, Houlden H, Rosser E, Limousin P, Kennedy A, Lunn MP, Bhatia KP, Wood NW, Hardy J, Polke JM, Veneziano L, Brusco A, Davis MB, Giunti P (2018) Complexity of the genetics and clinical presentation of Spinocerebellar Ataxia 17. Front Cell Neurosci 12:429.
  33. 33.
    Shin JH, Park H, Ehm GH, Lee WW, Yun JY, Kim YE, Lee JY, Kim HJ, Kim JM, Jeon BS, Park SS (2015) The pathogenic role of low range repeats in SCA17. PLoS One 10:e0135275. CrossRefGoogle Scholar
  34. 34.
    Kim JY, Kim SY, Kim JM, Kim YK, Yoon KY, Lee BC, Kim JS, Paek SH, Park SS, Kim SE, Jeon BS (2009) Spinocerebellar ataxia type 17 mutation as a causative and susceptibility gene in parkinsonism. Neurology 72:1385–1389. CrossRefGoogle Scholar
  35. 35.
    Craig K, Keers SM, Walls TJ, Curtis A, Chinnery PF (2005) Minimum prevalence of spinocerebellar ataxia 17 in the north east of England. J Neurol Sci 239:105–109. CrossRefGoogle Scholar
  36. 36.
    Sequeiros J, Seneca S, Martindale J (2010) Consensus and controversies in best practices for molecular genetic testing of spinocerebellar ataxias. Eur J Hum Genet 18:1188–1195. CrossRefGoogle Scholar
  37. 37.
    Liu Q, Zhang P, Wang D, Gu W, Wang K (2017) Interrogating the "unsequenceable" genomic trinucleotide repeat disorders by long-read sequencing. Genome Med 9:65.
  38. 38.
    Tang H, Kirkness EF, Lippert C, Biggs WH, Fabani M, Guzman E, Ramakrishnan S, Lavrenko V, Kakaradov B, Hou C, Hicks B, Heckerman D, Och FJ, Caskey CT, Venter JC, Telenti A (2017) Profiling of short-tandem-repeat disease alleles in 12,632 human whole genomes. Am J Hum Genet 101:700–715. CrossRefGoogle Scholar

Copyright information

© Fondazione Società Italiana di Neurologia 2020

Authors and Affiliations

  • Alessia Mongelli
    • 1
  • Stefania Magri
    • 1
  • Elena Salvatore
    • 2
  • Elena Rizzo
    • 1
  • Anna De Rosa
    • 2
  • Tommasina Fico
    • 2
  • Marta Gatti
    • 1
  • Cinzia Gellera
    • 1
  • Franco Taroni
    • 1
  • Caterina Mariotti
    • 1
    Email author
  • Lorenzo Nanetti
    • 1
  1. 1.Unit of Medical Genetics and NeurogeneticsFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly
  2. 2.Department of Neurosciences and Reproductive and Odontostomatological SciencesFederico II UniversityNaplesItaly

Personalised recommendations