We aimed to determine the origin and genetic characteristics of Huntington disease (HD) in the Middle East.
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.
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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $94.83 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
- Huntington disease
- juvenile-onset Huntington disease
- haplotype analysis