Expanding the spectrum of genes responsible for hereditary motor neuropathies. Issue 10 (5th June 2019)

• Record Type: Journal Article
• Authors: Previtali, Stefano C.; Zhao, Edward; Lazarevic, Dejan; Pipitone, Giovanni Battista; Fabrizi, Gian Maria; Manganelli, Fiore; Mazzeo, Anna; Pareyson, Davide; Schenone, Angelo; Taroni, Franco; Vita, Giuseppe; Bellone, Emilia; Ferrarini, Moreno; Garibaldi, Matteo; Magri, Stefania; Padua, Luca; Pennisi, Elena; Pisciotta, Chiara; Riva, Nilo; Scaioli, Vidmer; Scarlato, Marina; Tozza, Stefano; Geroldi, Alessandro; Jordanova, Albena; Ferrari, Maurizio; Molineris, Ivan; Reilly, Mary M.; Comi, Giancarlo; Carrera, Paola; Devoto, Marcella; Bolino, Alessandra;
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 90:Issue 10(2019)
• Page Start: 1171
• Page End: 1179
• Publication Date: 2019-06-05
• Subjects: Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2019-320717
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Background: Inherited 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. Methods: We 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. Results: Bioinformatic 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. Conclusions: These 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.