Excessive repeats of the hexaplet GGGGCC in intron 1 of the C9orf72 gene are the most frequent genetic mutations so far identified that are linked to amyotrophic lateral sclerosis (ALS) and frontot...

Pure cerebellar ataxia linked to large C9orf72 repeat expansion

With the disease modifying therapy Qalsody (tofersen) which targets the RNA product of the SOD1 gene, having been shown effective in amyotrophic lateral sclerosis (ALS), the present perspective seeks to explore progress towards the implementation of precision medicine principles in ALS drug development. We address the advances in our understanding of the complex genetic architecture of ALS, including the varying models of genetic contribution to disease, and the importance of understanding population genetics and genetic testing when considering patient selection for clinical studies. Additionally, we discuss the advances in long-read whole-genome sequencing technology and how this method can improve streamlined genetic testing and our understanding of the genetic heterogeneity in ALS. We highlight the recent advances in omics-data for understanding ALS patient sub-groups and how this knowledge should be applied to pre-clinical drug development in a proposed patient profiling workflow, particularly for gene targeted therapies. Finally, we summarise key ethical considerations that are pertinent to equitable care for patients, as we enter the era of precision medicine to treat ALS.

pdf/entering-the-era-of-precision-medicine-to-treat-amyotrophic-adaslbg1i5p4.pdf

Entering the era of precision medicine to treat amyotrophic lateral sclerosis

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 G4C2 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%, I2 = 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%, I2 = 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.

/pdf/c9orf72-hexanucleotide-repeat-in-huntington-like-patients-4z7iwbloe1.pdf

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

Expanding the spectrum of C9ORF72-related neurodegenerative disorders in the Greek population

When the genetic test for the Huntington’s disease (HD) HTT expansion first became available almost 30 years ago, only 1% of patients tested negative. Since then, the test has become more accessible and the HD phenotype has expanded. More patients are being tested overall, and more negative tests are being received. These patients are deemed “HD phenocopy syndromes” (HDPC). In this study we established a current estimate for the prevalence of these patients. We also surveyed HD clinician experts on what would make them consider an HD test and compared both HD and HDPC patients to these expectations to decide whether they could be distinguished clinically; this proved impossible even when comparing symptom patterns. We re-analysed existing gene panel data for likely and potentially deleterious variants. Furthermore, we determined principles to prioritise patients for whole-genome sequencing (WGS). It was used to probe a 50 patient strong subcohort of HD phenocopy syndromes for known causes of HD-like and other neurodegenerative disease, identifying one ATXN1 expansion using ExpansionHunter®. This was a small genetic substudy and therefore unsurprisingly no other known deleterious variants could be identified as in these cryptic understudied syndromes. Novel variants in known genes and variants in genes not yet linked to neurodegeneration may play an outsized role.

Huntington’s disease phenocopy syndromes revisited: a clinical comparison and next-generation sequencing exploration

Background In many cases where Huntington’s disease (HD) is suspected, the genetic test for HD is negative: these are known as HD phenocopies. Most of these individuals remain without a genetic diagnosis. A repeat expansion in the C9orf72 gene has been identified as the major cause of familial and sporadic frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Aim To determine whether the C9orf72 expansion mutation causes HD phenocopies. Methods A cohort of 514 HD phenocopy patients were analysed for the C9orf72 expansion using repeat-primed PCR. In cases where the expansion was found, Southern hybridisation was performed to determine expansion size. Clinical case notes were reviewed to determine the phenotype of expansion-positive cases. Results 10 subjects (1.95%) had the expansion, making it the commonest identified genetic cause of HD-phenocopy presentations. The size of expansion was not significantly different from that associated with other clinical presentations of C9orf72 expanded cases. The C9orf72 expansion-positive subjects were characterised by the presence of movement disorders including dystonia, chorea, myoclonus, tremor and rigidity. Furthermore the age of onset in this cohort was lower than previously reported for subjects with the C9orf72 expansion, and included one case with paediatric onset. Conclusions This study extends the known phenotype of the C9orf72 expansion, both in age of onset and movement disorder symptoms. We propose a revised clinico-genetic algorithm for the investigation of HD-phenocopy patients based on these data.

https://jnnp.bmj.com/content/jnnp/85/Suppl_1/A82.2.full.pdf

K11 C9orf72 Expansions Are The Most Common Genetic Cause Of Huntington’s Disease Phenocopy Presentations In A Uk Cohort

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Huntington’s disease phenocopy syndromes revisited: a clinical comparison and next-generation sequencing exploration

K11 C9orf72 Expansions Are The Most Common Genetic Cause Of Huntington’s Disease Phenocopy Presentations In A Uk Cohort