Tracing the mutated HTT and haplotype of the African ancestor who spread Huntington disease into the Middle East

Abstract

Purpose

We aimed to determine the origin and genetic characteristics of Huntington disease (HD) in the Middle East.

Methods

We performed genetic and genealogical analyses to establish the ancestral origin of the HTT pathgenic variant from a large kindred from Oman (hereafter called the OM-HD-01 pedigree) by single-nucleotide polymorphism and dense haplotype analysis genotyping.

Results

We traced the oldest ancestry of the largest, eight-generation, OM-HD-01 pedigree (n = 302 subjects, with 54 showing manifest HD) back to sub-Saharan Africa and identified a unique HD haplotype carried by all pedigree members, which consisted of portions of the C6 and C9 haplotypes and was carried by all affected members. Such a unique HD haplotype was of African origin and appeared to be associated with large CAG repeat expansions on average and high frequency of juvenile-onset HD. Three other families from the same area were also identified and found carrying a Caucasian HD haplotype A, also shared by most families of Arab ancestry.

Conclusion

Mutated HTT spread into Middle East with a unique haplotype of African origin, appeared to be associated with juvenile-onset, a HD condition frequently occurring in Black Africans, and may have a significant impact on further development of novel targeted genetic therapies.

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Fig. 1: Geographical ancestral migratory pathways between sub-Saharan Africa, and Oman, the Middle East.
Fig. 2: Haplotypes on control and expanded HTT alleles in Omani and South African Black patients.

References

  1. 1.

    Kay C, Collins JA, Wright GEB, et al. The molecular epidemiology of Huntington disease is related to intermediate allele frequency and haplotype in the general population. Am J Med Genet B. 2018;177:346–357.

    CAS  Article  Google Scholar 

  2. 2.

    Hayden MR, Hopkins HC, Macrea M, Beighton PH. The origin of Huntington’s chorea in the Afrikaner population of South Africa. S Afr Med J. 1980;58:197–200.

    CAS  PubMed  Google Scholar 

  3. 3.

    Baine FK, Kay C, Ketelaar ME, et al. Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes. Eur J Hum Genet. 2013;21:1120–1127.

    CAS  Article  Google Scholar 

  4. 4.

    Warby SC, Montpetit A, Hayden AR, et al. CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup. Am J Hum Genet. 2009;84:351–366.

    CAS  Article  Google Scholar 

  5. 5.

    Warby SC, Visscher H, Collins JA, et al. HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia. Eur J Hum Genet. 2011;19:561–566.

    CAS  Article  Google Scholar 

  6. 6.

    Li XY, Li HL, Dong Y, Gao B, et al. Haplotype analysis encompassing HTT gene in Chinese patients with Huntington’s disease. Eur J Neurol. 2020;27:273–279.

    Article  Google Scholar 

  7. 7.

    Kremer B, Goldberg P, Andrew SE, et al. A worldwide study of the Huntington’s disease mutation: the sensitivity and specificity of measuring CAG repeats. N Engl J Med. 1994;330:1401–1406.

    CAS  Article  Google Scholar 

  8. 8.

    Fusilli C, Migliore S, Mazza T, et al. Biological and clinical manifestations of juvenile Huntington’s disease: a retrospective analysis. Lancet Neurol. 2018;17:986–993.

    Article  Google Scholar 

  9. 9.

    Kay C, Collins JA, Skotte NH, et al. Huntingtin haplotypes provide prioritized target panels for allele-specific silencing in Huntington disease patients of European ancestry. Mol Ther. 2015;23:1759–1771.

    CAS  Article  Google Scholar 

  10. 10.

    Penney JB Jr, Vonsattel JP, Macdonald ME, Gusella JF, Myers RH. CAG repeat number governs the development rate of pathology in Huntington’s disease. Ann Neurol. 1997;41:689–692.

    Article  Google Scholar 

  11. 11.

    Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR, on behalf of an International Huntington’s Disease Collaborative Group. A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin Genet. 2004;65:267–277.

    CAS  Article  Google Scholar 

  12. 12.

    Kay C, Collins JA, Caron NS, et al. A comprehensive haplotype targeting strategy for allele-specific HTT suppression in Huntington disease. Am J Hum Genet. 2019;105:1112–1125.

    CAS  Article  Google Scholar 

  13. 13.

    Hayden MR, MacGregor JM, Saffer DS, Beighton PH. The high frequency of juvenile Huntington’s chorea in South Africa. J Med Genet. 1982;19:94–97.

    CAS  Article  Google Scholar 

  14. 14.

    Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. CAG repeat not polyglutamine length determines timing of Huntington’s disease onset. Cell. 2019;178:887–900.

    Article  Google Scholar 

  15. 15.

    Moss DJH, Pardiñas AF, Langbehn D, et al. Identification of genetic variants associated with Huntington’s disease progression: a genome-wide association study. Lancet Neurol. 2017;16:701–711.

    CAS  Article  Google Scholar 

  16. 16.

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

    Article  Google Scholar 

  17. 17.

    Telenius H, Kremer HPH, Thellmann J, et al. Molecular analysis of juvenile Huntington disease: the major influence on (CAG) n repeat length is the sex of the affected parent. Hum Mol Genet. 1993;2:1535–1540.

    CAS  Article  Google Scholar 

  18. 18.

    Goldstein O, Gana-Weisz M, Nefussy B, et al. High frequency of C9orf72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis patients from two founder populations sharing the same risk haplotype. Neurobiol Aging. 2018;64:e1–e7.

    Article  Google Scholar 

  19. 19.

    Krause A, Mitchell C, Essop F, et al. Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype. Am J Med Genet B. 2015;168:573–585.

    CAS  Article  Google Scholar 

  20. 20.

    Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al. Targeting Huntingtin expression in patients with Huntington’s disease. N Engl J Med. 2019;380:2307–2316.

    CAS  Article  Google Scholar 

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Acknowledgements

This study was financially supported by LIRH Foundation (funds from “5×1000” of taxes), by the Italian Ministry of Health (funds from Ricerca Finalizzata [RF-2016-02364123]), and by the Canadian Institutes of Health Research. We are grateful to Mohammed Al-Hajiri for careful and detailed historical assay of family OM-HD-01, and to Abigail Woollard, a professional medical writer funded by the LIRH Foundation, for providing editorial revisions to the manuscript.

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Correspondence to Ferdinando Squitieri MD, PhD.

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Disclosure

B.G.L. reports personal fees from AOP Orphan Pharmaceuticals, personal fees from Hoffmann-La Roche, grants from CHDI Foundation, other from Pfizer, other from Lundbeck, grants from JPND, grants from E-Rare, other from NeuraMetrix, personal fees from TEVA Pharmaceuticals, personal fees from Takeda, personal fees from Triplet TX, personal fees from PTC, personal fees from Sage Therapeutics, personal fees from Novartis, personal fees from Wave, outside the submitted work. F.S. provided consulting services and advisory board functions to Teva, Wave Pharma, Pfizer, Hoffmann-La Roche, Novartis, PTC Therapeutics, UCB, Oman Ministry of Health–Sultanate of Oman. He is cofounder, scientific officer, and consultant of the Italian League for Research on Huntington and related diseases (LIRH Foundation). The other authors declare no conflicts of interest.

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Squitieri, F., Mazza, T., Maffi, S. et al. Tracing the mutated HTT and haplotype of the African ancestor who spread Huntington disease into the Middle East. Genet Med (2020). https://doi.org/10.1038/s41436-020-0895-1

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Keywords

  • Huntington disease
  • juvenile-onset Huntington disease
  • haplotype analysis
  • SNP
  • HTT