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Loss of CAA interruption and intergenerational CAG instability in Chinese patients with Huntington’s disease

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Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG expansions in huntingtin (HTT) gene, involving motor, cognitive, and neuropsychiatric symptoms. However, genetic modifiers and CAG repeat instability may lead to variations of clinical manifestations, making diagnosis of HD difficult. In this study, we recruited 229 HD individuals from 164 families carrying expanded CAG repeats of HTT, and analyzed loss of CAA interruption (LOI) on the expanded allele and CAG instability during germline transmission. Sanger sequencing and TA cloning were used to determine CAG repeat length and identify LOI variants. Detailed clinical features and genetic testing results were collected. We identified 6 individuals with LOI variants from 3 families, and all probands presented with earlier motor onset age than predicted onset age. In addition, we also presented 2 families with extreme CAG instability during germline transmission. One family showed an expansion from 35 to 66 CAG repeats, while the other family showed both CAG expansion and contraction in lineal three generations. In conclusion, we present the first document of Asian HD population with LOI variant, and we suggest that for symptomatic individuals with intermediate or reduced penetrance allele or negative family history, HTT gene sequencing should be considered in the clinical practice.

Key messages

  • We screened the loss of CAA interruption (LOI) variant in a Chinese HD cohort and presented the first document of Asian patients with Huntington’s disease carrying LOI variant. We identified 6 individuals with LOI variants from 3 families, and all probands presented with earlier motor onset age than predicted onset age.

  • We presented 2 families with extreme CAG instability during germline transmission. One family showed an expansion from 35 to 66 CAG repeats, while the other family showed both CAG expansion and contraction in lineal three generations.

  • We suggest that for symptomatic individuals with intermediate or reduced penetrance allele or negative family history, HTT gene sequencing should be considered in the clinical practice.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Warby SC et al (2011) HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia. Eur J Hum Genet 19(5):561–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Li HL, Zhang YB, Wu ZY (2017) Development of research on Huntington disease in China. Neurosci Bull 33(3):312–316

    Article  PubMed  Google Scholar 

  3. Podvin S et al (2019) Multiple clinical features of Huntington’s disease correlate with mutant HTT gene CAG repeat lengths and neurodegeneration. J Neurol 266(3):551–564

    Article  CAS  PubMed  Google Scholar 

  4. Li HL et al (2019) Clinical and genetic profiles in Chinese patients with Huntington’s disease: a ten-year multicenter study in China. Aging Dis 10(5):1003–1011

    Article  PubMed  PubMed Central  Google Scholar 

  5. Langbehn DR et al (2004) A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin Genet 65(4):267–277

    Article  CAS  PubMed  Google Scholar 

  6. Warby SC et al (2009) CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup. Am J Hum Genet 84(3):351–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Becanovic K et al (2015) A SNP in the HTT promoter alters NF-kappaB binding and is a bidirectional genetic modifier of Huntington disease. Nat Neurosci 18(6):807–816

    Article  CAS  PubMed  Google Scholar 

  8. Kim KH et al (2020) Genetic and functional analyses point to FAN1 as the source of multiple Huntington disease modifier effects. Am J Hum Genet 107(1):96–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Flower M et al (2019) MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1. Brain 142(7):1876–1886

  10. Ciosi M et al (2019) A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes. EBioMedicine 48:568–580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li XY et al (2020) Haplotype analysis encompassing HTT gene in Chinese patients with Huntington’s disease. Eur J Neurol 27(2):273–279

    Article  PubMed  Google Scholar 

  12. Cheng HR et al (2020) Correlation between CCG polymorphisms and CAG repeats during germline transmission in chinese patients with Huntington’s disease. Neurosci Bull 36(7):811–814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li XY et al (2019) Effect of apolipoprotein E genotypes on Huntington’s disease phenotypes in a Han Chinese population. Neurosci Bull 35(4):756–762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Genetic Modifiers of Huntington’s Disease Consortium (2019) CAG repeat not polyglutamine length determines timing of Huntington’s disease onset. Cell 178(4):887–900 e14

  15. Wright GEB et al (2019) Length of uninterrupted CAG, independent of polyglutamine size, results in increased somatic instability, hastening onset of Huntington disease. Am J Hum Genet 104(6):1116–1126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wright GEB et al (2020) Interrupting sequence variants and age of onset in Huntington’s disease: clinical implications and emerging therapies. Lancet Neurol 19(11):930–939

    Article  CAS  PubMed  Google Scholar 

  17. Findlay Black H et al (2020) Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range. Genet Med 22(12):2108–2113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Houge G et al (2013) De novo Huntington disease caused by 26–44 CAG repeat expansion on a low-risk haplotype. Neurology 81(12):1099–1100

    Article  PubMed  PubMed Central  Google Scholar 

  19. Li XY et al (2022) The Chinese version of UHDRS in Huntington’s disease: reliability and validity assessment. J Huntingtons Dis 11(4):407–413

    Article  CAS  PubMed  Google Scholar 

  20. Ross CA et al (2014) Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol 10(4):204–216

    Article  CAS  PubMed  Google Scholar 

  21. Dong Y et al (2013) Chinese patients with Huntington’s disease initially presenting with spinocerebellar ataxia. Clin Genet 83(4):380–383

    Article  CAS  PubMed  Google Scholar 

  22. Green MR, Sambrook J (2021) Cloning polymerase chain reaction (PCR) products: TA cloning. Cold Spring Harb Protoc (6)

  23. Lee JM et al (2012) CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology 78(10):690–695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Watanabe M et al (2000) De novo expansion of a CAG repeat in a Japanese patient with sporadic Huntington’s disease. J Neurol Sci 178(2):159–162

    Article  CAS  PubMed  Google Scholar 

  25. Semaka A, Collins JA, Hayden MR (2010) Unstable familial transmissions of Huntington disease alleles with 27–35 CAG repeats (intermediate alleles). Am J Med Genet B Neuropsychiatr Genet 153B(1):314–320

    CAS  PubMed  Google Scholar 

  26. Semaka A et al (2013) CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease. J Med Genet 50(10):696–703

    Article  CAS  PubMed  Google Scholar 

  27. Zhou MY, Gomez-Sanchez CE (2000) Universal TA cloning. Curr Issues Mol Biol 2(1):1–7

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank all participants for their support and willingness to participate in this study. And we greatly appreciate all the patients and their families for volunteering their time and information.

Funding

This study was supported by the Key Research and Development Project of Zhejiang Province to Zhi-Ying Wu (2019C03039) and the research foundation for distinguished scholars of Zhejiang University to Zhi-Ying Wu (188020–193810101/089).

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Authors and Affiliations

  1. Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China

    Yu-Feng Bao, Xiao-Yan Li, Yi Dong & Zhi-Ying Wu

  2. Department of Neurology and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China

    Yu-Feng Bao, Xiao-Yan Li, Yi Dong & Zhi-Ying Wu

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  1. Yu-Feng Bao
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  2. Xiao-Yan Li
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Contributions

Data acquisition: YF. B. and XY. L.; statistical analysis and interpretation: YF. B., XY. L., and Y.D.; writing of the manuscript: YF. B.; revision of the manuscript: XY. L., Y.D. and ZY. W.; conception and design of the study: ZY. W. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zhi-Ying Wu.

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Ethical approval and consent to participate

For details and images relating to an individual person, written informed consent for publication was obtained. The study has passed the ethical approval of the Second Affiliated Hospital of Zhejiang University School of Medicine. This study conforms to the ethical guidelines of the Declaration of Helsinki.

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The authors declare no competing interests.

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Bao, YF., Li, XY., Dong, Y. et al. Loss of CAA interruption and intergenerational CAG instability in Chinese patients with Huntington’s disease. J Mol Med 101, 869–876 (2023). https://doi.org/10.1007/s00109-023-02329-0

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  • DOI: https://doi.org/10.1007/s00109-023-02329-0

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