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Research paper
Expanding the spectrum of genes responsible for hereditary motor neuropathies
  1. Stefano C. Previtali1,
  2. Edward Zhao2,
  3. Dejan Lazarevic3,
  4. Giovanni Battista Pipitone4,
  5. Gian Maria Fabrizi5,
  6. Fiore Manganelli6,
  7. Anna Mazzeo7,
  8. Davide Pareyson8,
  9. Angelo Schenone9,
  10. Franco Taroni10,
  11. Giuseppe Vita7,
  12. Emilia Bellone9,
  13. Moreno Ferrarini5,
  14. Matteo Garibaldi11,
  15. Stefania Magri10,
  16. Luca Padua12,
  17. Elena Pennisi13,
  18. Chiara Pisciotta8,
  19. Nilo Riva1,
  20. Vidmer Scaioli14,
  21. Marina Scarlato1,
  22. Stefano Tozza6,
  23. Alessandro Geroldi9,
  24. Albena Jordanova15,16,
  25. Maurizio Ferrari4,
  26. Ivan Molineris3,
  27. Mary M. Reilly17,
  28. Giancarlo Comi1,
  29. Paola Carrera4,
  30. Marcella Devoto2,18,
  31. Alessandra Bolino1
  1. 1 Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS Ospedale San Raffaele, Milano, Italy
  2. 2 Division of Genetics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  3. 3 Center for Translational Genomics and Bioinformatics, IRCCS Ospedale San Raffaele, Milano, Italy
  4. 4 Laboratory of Clinical and Molecular Biology and Unit of Genomics for Diagnosis of Genetic Diseases, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milano, Italy
  5. 5 Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
  6. 6 Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Napoli, Italy
  7. 7 Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
  8. 8 Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
  9. 9 Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal Infantile Sciences, University of Genoa, and IRCCS Policlinico San Martino, Genova, Italy
  10. 10 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
  11. 11 Unit of Neuromuscular Disorders, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Sapienza University of Rome, Sant'Andrea Hospital, Roma, Italy
  12. 12 Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica, Roma, Italy
  13. 13 Ospedale San Filippo Neri, Roma, Italy
  14. 14 Neurophysiopathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
  15. 15 VIB-UAntwerp Center for Molecular Neurology, Antwerp, Belgium
  16. 16 Department of Medical Chemistry and Biochemistry, Medical University-Sofia, Sofia, Bulgaria
  17. 17 MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
  18. 18 Department of Translational and Precision Medicine, University La Sapienza, Roma, Italy
  1. Correspondence to Dr. Alessandra Bolino, Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS Ospedale San Raffaele, Milano, Italy; bolino.alessandra{at}; Dr Stefano C. Previtali, Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS Ospedale San Raffaele, Milano, Italy; previtali.stefano{at}


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.