Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes

Abstract

Huntington disease (HD) is a neurodegenerative disorder resulting from the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. Worldwide prevalence varies geographically with the highest figures reported in populations of European ancestry. HD in South Africa has been reported in Caucasian, black and mixed subpopulations, with similar estimated prevalence in the Caucasian and mixed groups and a lower estimate in the black subpopulation. Recent studies have associated specific HTT haplotypes with HD in distinct populations. Expanded HD alleles in Europe occur predominantly on haplogroup A (specifically high-risk variants A1/A2), whereas in East Asian populations, HD alleles are associated with haplogroup C. Whether specific HTT haplotypes associate with HD in black Africans and how these compare with haplotypes found in European and East Asian populations remains unknown. The current study genotyped the HTT region in unaffected individuals and HD patients from each of the South African subpopulations, and haplotypes were constructed. CAG repeat sizes were determined and phased to haplotype. Results indicate that HD alleles from Caucasian and mixed patients are predominantly associated with haplogroup A, signifying a similar European origin for HD. However, in black patients, HD occurs predominantly on haplogroup B, suggesting several distinct origins of the mutation in South Africa. The absence of high-risk variants (A1/A2) in the black subpopulation may also explain the reported low prevalence of HD. Identification of haplotypes associated with HD-expanded alleles is particularly relevant to the development of population-specific therapeutic targets for selective suppression of the expanded HTT transcript.

REVIEW-ARTICLE Intermediate alleles of Huntington’s disease HTT gene in different populations worldwide: a systematic review

“…Regarding haplogroups and IAs in South Africa, it was observed that individuals with IA with family history of HD belonged to haplogroup C (Baine et al, 2013). Furthermore, other article reports the investigation of haplotypes A, B, and C carried out in the general population of Thailand, where it was observed that individuals with IAs had haplogroups not associated with HD such as A (variant A5 and haplogroup C).…”

“…The frequency of IAs/total chromosomes reported in the articles, considering the general population, ranged from 0.45 to 8.7% (Raskin et al, 2000;Pulkes et al, 2014) and the frequencies of individuals who bore IAs and had family history of HD ranged from 0.05 to 5.1% (Raskin et al, 2000;Baine et al, 2013;Killoran et al, 2013;Pulkes et al, 2014).…”

The targetable A1 Huntington disease haplotype has distinct Amerindian and European origins in Latin America

“…4,5 In populations of European ancestry where prevalence is highest, the expanded CAG repeat occurs preferentially on haplotypes A1, A2, and A3a, whereas in African and East Asian patients the HD mutation occurs on a heterogeneous mix of local haplotypes. [6][7][8][9] European HD haplotypes A1 and A2 do not occur in African and East Asian populations, suggesting that these haplotypes may account in part for higher HD prevalence rates in populations of European ancestry. 4,7 HD has been reported in many countries of Latin America, but detailed genetic investigations are lacking.…”

Understanding the genetic diversity of South Africa’s peoples

“…HD due to mutations in the HTT gene occurs, but on African-specific haplotypes that differ from those in white patients. [15] In addition, a second HD gene (JPH3) has been implicated in African patients with an HD-like phenotype (HDL2), who do not have an expansion in the HTT gene. Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many individual cases, although the average age of onset and diagnosis in HDL2 is approximately 5 years later than HD and individual clinical features may be more prominent.…”