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.
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Contributors Study concept and design: SCP and AB. Acquisition, analysis and interpretation of data: SCP, EZ, DL, GP, GMF, FM, AM, DP, AS, FT, GV, EB, MoF, MG, SM, LP, EMP, CP, NR, VS, MS, ST, AG, AJ, MaF, IM, MMR, GC, PC, MD and AB. Drafting of the manuscript: SCP, MMR, MD and AB.
Funding This work was supported by the Italian Ministry of Health (RF-2011-02347127) and the CoFin Regione Lombardia (No. 96).
Competing interests None declared.
Patient and public involvement statement Patients gave informed consent to clinical and genetic studies according to respective national regulations.
Patient consent for publication Obtained.
Ethics approval Board name: Comitato Etico, Ospedale San Raffaele Milano, ID No. BANCA-INSPE, 30 October 2009.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request.