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

Abstract

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.

Increased frequency of repeat expansion mutations across different populations

“…4A, Table S17). In agreement with current known epidemiological studies, we observed that pathogenic alleles in 11,[37][38][39][40] . Given that the initial ancestry assignments for our cohort were based on genome-wide data, we performed local ancestry analysis to check for admixture in these individuals, confirming that the expanded repeat alleles segregated on haplotypes of African and South Asian ancestry (Methods).…”