A study of Huntington disease-like syndromes in black South African patients reveals a single SCA2 mutation and a unique distribution of normal alleles across five repeat loci

Baine, Fiona; Peerbhai, Nabeelah; Krause, Amanda

doi:10.1016/j.jns.2018.04.031

Cited by 9 publications

(11 citation statements)

References 36 publications

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“…In addition, low frequencies of C9-expansion alleles were found in Europeans with other neurodegenerative diseases including Huntington's diseaselike syndromes (7/421; 1.6%) [3]. A study confined to black South Africans (n=97), in which C9orf72 alleles were sized in a lab-based sample of possible "Huntington disease" (HD) phenocopies (both HD1 and HD2 mutations were excluded), found all the C9orf72 repeat alleles in that cohort within the 2-11 repeat range [22]. Here we add an 45 additional SA-controls with African genetic ancestry, who underwent WGS, and found no C9orf72 expansion mutations.…”

Section: Discussionmentioning

confidence: 99%

C9orf72 repeat expansions in South Africans with amyotrophic lateral sclerosis

Nel

Agenbag

Henning

et al. 2019

Journal of the Neurological Sciences

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The hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic variant found in individuals with sporadic amyotrophic lateral sclerosis (ALS), occurring at a frequency of between 7-11% in cohorts of European ancestry. While limited data suggest that C9-expansions (>30 repeats) are less frequent in African-Americans with ALS, there is no data on the frequency of C9-expansions among ALS subjects residing in Africa. We therefore investigated the frequency of this expansion mutation (using repeat-primed PCR) in a cohort of 143 South Africans (SA) with ALS. The cohort included different genetic ancestry subgroups who self-identified as black African (n=24), Cape mixed-African (M/A) (n=65), white European ancestry (n=51), and Indian ancestry (n=3). Three M/A individuals had a family history of ALS (2%) and all had normal C9orf72 alleles. Of the 140 individuals with sporadic ALS who were successfully genotyped, 10 (7%) carried pathogenic C9-expansions; four white and six M/A ancestry individuals, respectively. Our results highlight the importance of including Africans in genetic studies aimed at unravelling the genomic architecture in ALS and suggest pathogenetic mechanisms other than the C9orf72 expansion in black Africans with ALS.

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Section: Discussionmentioning

confidence: 99%

C9orf72 repeat expansions in South Africans with amyotrophic lateral sclerosis

Nel

Agenbag

Henning

et al. 2019

Journal of the Neurological Sciences

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“…The updated search conducted ~2 years later yielded seven additional titles from Pubmed. Three of these new findings were included in the full-text review, and finally, all of them were included in the systematic synthesis (Baine et al, 2018 ; Ida et al, 2018 ). Two additional studies were identified through other sources.…”

Section: Resultsmentioning

confidence: 99%

“…This systematic review was conducted in four primary publication databases and found 10 studies that reported the C9orf72 pathogenic repeat expansion frequency among patients diagnosed with HLD (Hensman Moss et al, 2014a;Kostic et al, 2014;Koutsis et al, 2015;Fedotova et al, 2016;Mariani et al, 2016;Baine et al, 2018;Ida et al, 2018;Martins et al, 2018a;Rikos et al, 2020). Most of these cases were referred with a clinical diagnosis of Huntington Disease by an expert neurologist or neurogeneticist for the (CAG)n-HTT expansion test.…”

Section: Discussionmentioning

confidence: 99%

“…Two studies did not mention the diagnostic criteria for HLD (Fedotova et al, 2016;Kaur et al, 2020). At least six studies described a diagnostic workup that excluded other genetic causes of HLD including neuroacanthocytosis, neurodegeneration with brain iron accumulation, DJ-1 mutations, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease, HLD type 2, SCA-1, SCA-2, SCA-3, SCA-7, SCA-8, SCA-12, SCA-10, SCA-17, dentatorubral-pallidoluysian atrophy, and familial prion disease (Kostic et al, 2014;Koutsis et al, 2015;Mariani et al, 2016;Baine et al, 2018;Martins et al, 2018a;Rikos et al, 2020).…”

Section: Studies Characteristicsmentioning

confidence: 99%

“…We conducted a cumulative analysis of six studies, excluding studies that reported no HLD patients with the C9orf72 hexanucleotide repeat expansion (Fedotova et al, 2016;Mariani et al, 2016;Baine et al, 2018). The overall frequency of the expansion was 1% (95% CI: 1-2%, I 2 = 0%, p = 0.58) (Figure 4).…”

Section: Sensitivity Analysismentioning

confidence: 99%

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C9orf72 Hexanucleotide Repeat in Huntington-Like Patients: Systematic Review and Meta-Analysis

et al. 2020

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Introduction: Patients with Huntington-Like disorders (HLD) comprise a variety of allelic disorders sharing a Huntington phenotype. The hexanucleotide repeat expansion of the C9orf72 gene could explain part of the HLD etiology. We aimed to conduct a systematic review and meta-analysis looking for the frequency of the hexanucleotide repeat expansion of the C9orf72 gene in HLD patients. Methods: The protocol was registered on the International Prospective Register of Systematic Reviews database (PROSPERO) (registration number: CRD42018105465). The search was carried out in Medline, Scopus, Web of Science, and Embase in April 2018, and updated in July 2020. Observational studies reporting patients with HLD carrying the hexanucleotide repeat expansion in the C9orf72 gene were selected and reviewed; this process was duplicated. The cutoff threshold for considering the hexanucleotide expansion as a pathogenic variant was equal to or >30 G 4 C 2 repeats. Cases with intermediate alleles with 20-29 repeat are also analyzed. Pooled frequency and 95% CI were calculated using random-effects models. Results: Nine out of 219 studies were selected, reporting 1,123 affected individuals with HLD. Among them, 18 individuals carried C9orf72 expansion, representing 1% (95% CI: 0-2%, I 2 = 0%) of the pooled frequency. Seven selected studies came from European centers, one was reported at a US center, and one came from a South-African center. We identified five individuals carrying intermediate alleles representing 3% (95% CI: 0-14%, I 2 = 78.5%). Conclusions: The frequency of C9orf72 unstable hexanucleotide repeat expansion in HLD patients is very low. Further studies with more accurate clinical data and from different ethnic backgrounds are needed to confirm this observation.

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Huntington’s disease: lessons from prion disorders

Alpaugh

Cicchetti

2021

J Neurol

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A study of Huntington disease-like syndromes in black South African patients reveals a single SCA2 mutation and a unique distribution of normal alleles across five repeat loci

Cited by 9 publications

References 36 publications

C9orf72 repeat expansions in South Africans with amyotrophic lateral sclerosis

C9orf72 repeat expansions in South Africans with amyotrophic lateral sclerosis

C9orf72 Hexanucleotide Repeat in Huntington-Like Patients: Systematic Review and Meta-Analysis

Huntington’s disease: lessons from prion disorders

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