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



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.

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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.


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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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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).

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