Ferdinando Squitieri1, Tommaso Mazza2, Sabrina Maffi3, Alessandro De Luca4, Qasem AlSalmi5, Salma AlHarasi5, Jennifer A Collins6, Chris Kay6, Fiona Baine-Savanhu7, Bernard G Landwhermeyer8, Umberto Sabatini9,10, Michael R Hayden6. 1. Huntington and Rare Diseases Unit, Fondazione IRCCS Casa Sollievo della Sofferenza Research Hospital, San Giovanni Rotondo, Italy. f.squitieri@css-mendel.it. 2. Bioinformatics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza Research Hospital, San Giovanni Rotondo, Italy. 3. Huntington and Rare Diseases Unit, Fondazione IRCCS Casa Sollievo della Sofferenza Research Hospital, San Giovanni Rotondo, Italy. 4. Medical Genetics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza Research Hospital, San Giovanni Rotondo, Italy. 5. National Genetic Centre, Royal Hospital, Ministry of Health, Muscat, Sultanate of Oman. 6. Centre for Molecular Medicine Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. 7. NHLS & School of Pathology, University of the Witwatersrand, Johannesburg, South Africa. 8. Abteilung Neurologie, Universitätsklinik Ulm, Ulm, Germany. 9. Department of Neuroradiology, University Magna Graecia, Catanzaro, Italy. 10. Italian League for Research on Huntington Disease (LIRH) Foundation, Rome, Italy.
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.
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.