An exploration of the genetics of the mutant Huntingtin (mHtt) gene in a cohort of patients with chorea from different tribes in 6 sub-Saharan African countries

Background Africans are underrepresented in Huntington’s disease research. A European ancestor was postulated to have introduced the mutant Huntingtin ( mHtt ) gene to the continent, however recent work has shown the existence of a unique Huntingtin haplotype in South-Africa specific to indigenous Africans. Objective We aimed to investigate the CAG repeats expansion in the Huntingtin ( Htt ) gene in a geographically diverse cohort of patients with chorea and unaffected controls from sub-Saharan Africa. Methods We evaluated 104 participants: 45 patients with chorea, 24 asymptomatic first-degree relatives of subjects with chorea and 35 healthy controls for the presence of the mHtt . Participants were recruited from 6 African countries. Additional data were collected from patients positive for the mHtt including demographics, presence of psychiatric and cognitive symptoms, family history, spoken languages and tribal origin. Additionally, their pedigrees were examined to estimate the number of people at risk of developing HD and to trace back the earliest account of the disease in each region. Results HD cases were identified in all countries. 53.3% of patients with chorea were carriers for the mHTT ; median tract size 45 CAG repeats. Of the asymptomatic relatives 41.6% were carriers for the mHTT; median tract size 42.5 CAG. No homozygous carries were identified. Median CAG tract size in controls was 17 CAG repeats. Men and women were equally affected by HD. All patients with HD—bar three who were juvenile onset of <21 years—were defined as adult onset (median age of onset 40 years). HD transmission followed an autosomal dominant pattern in 80% (16/20) of HD families. In familial cases, maternal transmission was higher (56%) than paternal transmission (44%). The number of asymptomatic individuals at risk of developing HD was estimated at 10 times more than the symptomatic patients. HD could be traced back to the early 1900s in most African sites. HD cases spread over 8 tribes belonging to two distinct linguistic lineages separated from each other approximately 37 kya ago: Nilo-Sahara and Niger-Congo. Conclusion This is the first study examining HD in multiple sites in sub-Saharan Africa. We demonstrated that HD is found in multiple tribes residing in 6 sub-Saharan African countries including the first genetically confirmed HD cases from Guinea and Kenya. The prevalence of HD in the African continent, its associated socio-economic impact, and genetic origins need further exploration and reappraisal. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: the ethics committee of the University College London and the National Hospital for Neurology and Neurosurgery, London, UK Ethics approval # 07/Q0512/26 and The Institutional Scientific and Ethics Review Committee of The Aga Khan University, Nairobi, Kenya waived ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors