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.

Huntington disease (HD) is the most common monogenic neurodegenerative disorder in populations of European ancestry, but occurs at lower prevalence in populations of East Asian or black African descent. New mutations for HD result from CAG repeat expansions of intermediate alleles (IAs), usually of paternal origin. The differing prevalence of HD may be related to the rate of new mutations in a population, but no comparative estimates of IA frequency or the HD new mutation rate are available. In this study, we characterize IA frequency and the CAG repeat distribution in fifteen populations of diverse ethnic origin. We estimate the HD new mutation rate in a series of populations using molecular IA expansion rates. The frequency of IAs was highest in Hispanic Americans and Northern Europeans, and lowest in black Africans and East Asians. The prevalence of HD correlated with the frequency of IAs by population and with the proportion of IAs found on the HD-associated A1 haplotype. The HD new mutation rate was estimated to be highest in populations with the highest frequency of IAs. In European ancestry populations, one in 5,372 individuals from the general population and 7.1% of individuals with an expanded CAG repeat in the HD range are estimated to have a molecular new mutation. Our data suggest that the new mutation rate for HD varies substantially between populations, and that IA frequency and haplotype are closely linked to observed epidemiological differences in the prevalence of HD across major ancestry groups in different countries.

Huntington disease (HD) is a fatal neurodegenerative disorder caused by a gain-of-function mutation in HTT. Suppression of mutant HTT has emerged as a leading therapeutic strategy for HD, with allele-selective approaches targeting HTT SNPs now in clinical trials. Haplotypes associated with the HD mutation (A1, A2, A3a) represent panels of allele-specific gene silencing targets for efficient treatment of individuals with HD of Northern European and indigenous South American ancestry. Here we extend comprehensive haplotype analysis of the HD mutation to key populations of Southern European, South Asian, Middle Eastern, and admixed African ancestry. In each of these populations, the HD mutation occurs predominantly on the A2 HTT haplotype. Analysis of HD haplotypes across all affected population groups enables rational selection of candidate target SNPs for development of allele-selective gene silencing therapeutics worldwide. Targeting SNPs on the A1 and A2 haplotypes in parallel is essential to achieve treatment of the most HD-affected subjects in populations where HD is most prevalent. Current allele-specific approaches will leave a majority of individuals with HD untreated in populations where the HD mutation occurs most frequently on the A2 haplotype. We further demonstrate preclinical development of potent and selective ASOs targeting SNPs on the A2 HTT haplotype, representing an allele-specific treatment strategy for these individuals. On the basis of comprehensive haplotype analysis, we show the maximum proportion of HD-affected subjects that may be treated with three or four allele targets in different populations worldwide, informing current allele-specific HTT silencing strategies.

The Mesembryanthemoideae and Ruschioideae subfamilies are a major component of the Greater Cape Floristic Region in southern Africa. The Ruschioideae show an astonishing diversity of leaf shape and growth forms. Although 1,585 species are recognised within the morphologically diverse Ruschioideae, these species show minimal variation in plastid DNA sequence. We have investigated whether changes in selected leaf development transcription factors underpin the recent, rapid diversification of this large group of succulent plants. Degenerate primers designed to conserved regions of Asymmetric Leaves1/Rough Sheath 2/Phantastica (ARP) and the Class III HD-ZIP family of genes, were used to amplify sequences corresponding to these genes from several species within the Mesembryanthemoideae and Ruschioideae subfamilies. Two members of the Class III HD-ZIP family were identified in both the Mesembryanthemoideae and Ruschioideae, and were derived from an ancient gene duplication event that preceded the divergence of gymnosperms and angiosperms. While a single ARP orthologue was identified in the Mesembryanthemoideae, two paralogues, ARPa and ARPb, were identified in the Ruschioideae subfamily. ARPa was present in all species of Ruschioideae analysed in this study. ARPb has been lost from the Apatesieae and Dorotheantheae tribes, which form an early evolutionary branch from the Ruschieae tribe, as well as from selected species within the Ruschieae. The recent duplication and subsequent selected gene loss of the ARP transcription factor correlates with the rapid diversification of plant forms in the Ruschioideae.

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Background: Fluorescent in situ Hybridisation (FISH) is a valuable option for follow-up or confirmatory testing especially if aberrations have been missed or require further testing for interpretation after array comparative genomic hybridisation (aCGH). In this study, the Vysis IntelliFISH Hybridization Buffer (Abbott Molecular Inc.) hybridisation protocol was successfully validated with improved turn-around-time and the utility of FISH as a follow-up test for patients referred for aCGH testing was evaluated. Results: The results for nine of 11 selected cases correlated with the aCGH findings. Of these, six were for 22q11.2 deletion syndrome, two for Wolf-Hirschhorn syndrome and one for Prader-Willi/Angelman syndrome. In addition, two cases were negative on aCGH but were positive for Pallister-Killian syndrome on FISH, confirming the clinical diagnosis. Conclusion: Offering FISH as a follow-up test to aCGH is beneficial in specific circumstances i.e., in tissue-specific mosaicism as illustrated by the PKS cases, or for family cascade testing of a confirmed microdeletion or microduplication. Genetics laboratories should consider implementing FISH studies as a follow-up test for post-natal microarray results.

BackgroundHuntington’s disease (HD) is caused by an unstable expanded trinucleotide (CAG) repeat in the huntingtin (HTT) gene. Presentation involves a clinical triad of symptoms: behavioural problems, movement disorder and cognitive decline. Elsewhere, between 1 and 7% of individuals diagnosed do not carry the mutation and are said to have an HD phenocopy; a term used to describe any syndrome that manifests HD-like symptoms in the absence of an HTT expansion. In South Africa, direct mutation testing is performed in the public sector by the National Health Laboratory Service. Approximately 30% of patients referred for confirmation of an HD diagnosis do not carry an HTT expansion. Huntington’s disease-like 2 (HDL2) has recently been incorporated into routine diagnostic testing for HD referrals as up to one third of patients negative for the HTT expansion were found to carry an expansion in the underlying junctophilin-3 (JPH3) gene. AimTo investigate the occurrence of mutations associated with HD phenocopies in a cohort of black South African individuals.MethodsRecords revealed 105 individuals with negative results for the HTT and JPH3 expansions. Molecular screening was performed for: Spinocerebellar ataxia (SCA) subtypes: 1, 2, 7, 17; Dentatorubral-palidolluysian atrophy (DRPLA) and C9orf72 hexanucleotide expansions.ResultsThus far a single expansion has been identified confirming SCA2 and results are pending for the C9orf72 screen.ConclusionsMutations associated with HD phenocopies appear to be absent in this cohort and may indicate the presence of novel genes and/mutations causing the HD-like phenotype.