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.

Expanding the spectrum of genes responsible for hereditary motor neuropathies / Previtali, S. C.; Zhao, E.; Lazarevic, D.; Pipitone, G. B.; Fabrizi, G. M.; Manganelli, F.; Mazzeo, A.; Pareyson, D.; Schenone, A.; Taroni, F.; Vita, G.; Bellone, E.; Ferrarini, M.; Garibaldi, M.; Magri, S.; Padua, L.; Pennisi, E.; Pisciotta, C.; Riva, N.; Scaioli, V.; Scarlato, M.; Tozza, S.; Geroldi, A.; Jordanova, A.; Ferrari, M.; Molineris, I.; Reilly, M. M.; Comi, G.; Carrera, P.; Devoto, M.; Bolino, A.. - In: JOURNAL OF NEUROLOGY, NEUROSURGERY AND PSYCHIATRY. - ISSN 0022-3050. - 90:10(2019), pp. 1171-1179. [10.1136/jnnp-2019-320717]

Expanding the spectrum of genes responsible for hereditary motor neuropathies

Garibaldi M.;Devoto M.;
2019

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.
2019
Inherited peripheral neuropathies
01 Pubblicazione su rivista::01a Articolo in rivista
Expanding the spectrum of genes responsible for hereditary motor neuropathies / Previtali, S. C.; Zhao, E.; Lazarevic, D.; Pipitone, G. B.; Fabrizi, G. M.; Manganelli, F.; Mazzeo, A.; Pareyson, D.; Schenone, A.; Taroni, F.; Vita, G.; Bellone, E.; Ferrarini, M.; Garibaldi, M.; Magri, S.; Padua, L.; Pennisi, E.; Pisciotta, C.; Riva, N.; Scaioli, V.; Scarlato, M.; Tozza, S.; Geroldi, A.; Jordanova, A.; Ferrari, M.; Molineris, I.; Reilly, M. M.; Comi, G.; Carrera, P.; Devoto, M.; Bolino, A.. - In: JOURNAL OF NEUROLOGY, NEUROSURGERY AND PSYCHIATRY. - ISSN 0022-3050. - 90:10(2019), pp. 1171-1179. [10.1136/jnnp-2019-320717]
File allegati a questo prodotto
File Dimensione Formato  
Previtali_motor_neuropathies_2019.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 1.97 MB
Formato Adobe PDF
1.97 MB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1307647
Citazioni
  • ???jsp.display-item.citation.pmc??? 13
  • Scopus 32
  • ???jsp.display-item.citation.isi??? 30
social impact