• Stefano C Previtali, Edward Zhao, Dejan Lazarevic, Giovanni Battista Pipitone, Gian Maria Fabrizi, Fiore Manganelli, Anna Mazzeo, Davide Pareyson, Angelo Schenone, Franco Taroni, Giuseppe Vita, Emilia Bell... more one, Moreno Ferrarini, Matteo Garibaldi, Stefania Magri, Luca Padua, Elena Pennisi, Chiara Pisciotta, Nilo Riva, Vidmer Scaioli, Marina Scarlato, Stefano Tozza, Alessandro Geroldi, Albena Jordanova, Maurizio Ferrari, Ivan Molineris, Mary M Reilly, Giancarlo Comi, Paola Carrera, Marcella Devoto, and Alessandra Bolino. less
• Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS Ospedale San Raffaele, Milano, Italy bolino.alessandra@hsr.it previtali.stefano@hsr.it.
• J. Neurol. Neurosurg. Psychiatr. 2019 Oct 1; 90 (10): 117111791171-1179.

BackgroundInherited peripheral neuropathies (IPNs) represent a broad group of genetically and clinically heterogeneous disorders, including axonal Charcot-Marie-Tooth type 2 (CMT2) and hereditary motor neuropathy (HMN). Approximately 60%-70% of cases with HMN/CMT2 still remain without a genetic diagnosis. Interestingly, mutations in HMN/CMT2 genes may also be responsible for motor neuron disorders or other neuromuscular diseases, suggesting a broad phenotypic spectrum of clinically and genetically related conditions. Thus, it is of paramount importance to identify novel causative variants in HMN/CMT2 patients to better predict clinical outcome and progression.MethodsWe designed a collaborative study for the identification of variants responsible for HMN/CMT2. We collected 15 HMN/CMT2 families with evidence for autosomal recessive inheritance, who had tested negative for mutations in 94 known IPN genes, who underwent whole-exome sequencing (WES) analyses. Candidate genes identified by WES were sequenced in an additional cohort of 167 familial or sporadic HMN/CMT2 patients using next-generation sequencing (NGS) panel analysis.ResultsBioinformatic analyses led to the identification of novel or very rare variants in genes, which have not been previously associated with HMN/CMT2 (ARHGEF28, KBTBD13, AGRN and GNE); in genes previously associated with HMN/CMT2 but in combination with different clinical phenotypes (VRK1 and PNKP), and in the SIGMAR1 gene, which has been linked to HMN/CMT2 in only a few cases. These findings were further validated by Sanger sequencing, segregation analyses and functional studies.ConclusionsThese results demonstrate the broad spectrum of clinical phenotypes that can be associated with a specific disease gene, as well as the complexity of the pathogenesis of neuromuscular disorders.© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

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