Abstract
Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series. The correct gene was predicted in 61 and 78 % of the cases by the two assessors, respectively. There was a high inter-rater agreement [K = 0.85 (0.55–0.98) p < 0.001] confirming the algorithm’s reproducibility. Phenotyping patients with proper clinical examination, imaging, biochemical investigations and nerve conduction studies remain crucial for the guidance of molecular analysis and to interpret next generation sequencing results. The proposed algorithm should be helpful for diagnosing ARCA in clinical practice.
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Acknowledgments
Sequencing was performed by the IGBMC Microarray and Sequencing platform a member of the “France Génomique” consortium (ANR-10-INBS-0009). This study was supported by funds from the Agence Nationale pour la Recherche-Maladies Rares and Maladies Neurologiques et Psychiatriques (ANR-09-MNPS-001-01 to M.K. and A.D.) the ANR/E-rare JTC 2011 “Euro-SCAR” (2011-RARE-004-01 to M.K.) and the Agence de la Biomédecine (to J.-L.M.). M.R. was supported by a fellowship from the “Journées de Neurologie de Langue Française”.
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The authors declare no financial disclosure related to the research covered by this article. Martial Mallaret received travel grants from Ipsen and Merz. Mathieu Anheim received honoraria and travel grants from Actelion.
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M. Anheim and M. Koenig equally contributed to this work.
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415_2016_8112_MOESM1_ESM.docx
Supplementary file: A-Panel of 57 ataxia mutated genes (in alphabetical order). B- Variants Analysis of NGS data. C-Clinical and molecular data of the patients without evaluation by the clinical practice-based algorithm. D- Comparative clinical data from patients with a molecular diagnosis (positive patients) and without (negative patients) in our series (DOCX 26 kb)
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Mallaret, M., Renaud, M., Redin, C. et al. Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases. J Neurol 263, 1314–1322 (2016). https://doi.org/10.1007/s00415-016-8112-5
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DOI: https://doi.org/10.1007/s00415-016-8112-5