Screening for the C9ORF72 expansion in Greek Huntington Disease phenocopies and controls and meta-analysis of current data.

Thomas Bourinaris,George M. Hadjigeorgiou,Georgia Xiromerisiou,Efthimios Dardiotis,Pantelis Stathis,Dimitrios Rikos,Antonios Provatas,George P. Patrinos,Chrysoula Marogianni,Marianthi Arnaoutoglou

doi:10.5334/tohm.61

Abstract

Background:Several European studies examined the role of C9orf72 repeat expansion in patients with Huntington-disease like phenotypes (HD-L). The scope of our study is to investigate the expansion frequency in a Greek HD-L cohort and the meta-analysis of all published cases. This will be of use in genetic counseling of these cases.Methods:A cohort of 74 patients with HD-L and 67 healthy controls were screened for the C9orf72 expansion status. Case-controls comparison was assessed with the Pearson’s chi-square statistic for a 2 × 2 table.A systematic database search was conducted and seven studies, including the current study, were considered eligible for inclusion in a meta-analysis considering a total of 812 patients with HD phenocopies. Pooled mutation frequency was calculated using a Random Effects model or the Mantel-Haezsel fixed effects model, depending on the observed heterogeneity.Results:In our cohort, one patient was found to have a pathologic expansion of C9orf72, and none from the control group (chi-square: 0.91, p-value: 0.34). Pooled mutation frequency was found at 2% (CI: 1–3%) with low heterogeneity (I2:15%).Discussion:Based on this meta-analysis the recommendation for genetic testing for C9orf72 expansions is further solidified.

Highlights

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene [1]
We aim to investigate the frequency of C9orf72 expansions in a cohort of patients with an HD-like disorder
Based on the revealing results concerning ALS, FTD and C9orf72 mutation, genetic datasets of patients suffering from HD-like disorders were analyzed in search for this hexanucleotide expansion, demonstrating interesting results [22]

Summary

Introduction

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene [1]. Rikos et al: Screening for the C9ORF72 Expansion in Greek Huntington Disease Phenocopies and Controls and Meta-analysis of Current Data manifested with the HD phenotype, such as “HDL1” (caused by an 8-octapeptide insertion in the PRNP gene), “HDL2” (caused by mutations in JPH3) and “HDL4” (SCA17). It is crucial for clinicians to identify the genetic basis of HDL disorders, in order to organize our therapeutic strategy for the patients and provide education for their families and them It can enrich the search for Huntington’s disease modifiers. In the search for possible responsible genes for HDL disorders, it was found that SCA17 accounts for 1.1%, HDL2 for 0.7%, Friedreich ataxia for 0.35% and inherited prion disease for 0.24% of HD phenocopies This search is constantly expanding, most of the included diseases in the spectrum of HD like, fail to reach a robust genetic diagnosis [3]. Discussion: Based on this meta-analysis the recommendation for genetic testing for C9orf expansions is further solidified

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