Expanding the spectrum of genes responsible for hereditary motor neuropathies

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 Bellone, Moreno Ferrarini, Matteo Garibaldi, Stefania Magri, Luca Padua, Elena Pennisi, Chiara Pisciotta, Nilo Riva, Vidmer ScaioliMarina Scarlato, Stefano Tozza, Alessandro Geroldi, Albena Jordanova, Maurizio Ferrari, Ivan Molineris, Mary M. Reilly, Giancarlo Comi, Paola Carrera, Marcella Devoto, Alessandra Bolino

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalJournal of Neurology, Neurosurgery and Psychiatry
DOIs
Publication statusPublished - Jan 1 2019

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Charcot-Marie-Tooth Disease
Genes
Exome
Phenotype
Neuromuscular Diseases
Mutation
Motor Neurons
Computational Biology
Tooth

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology
  • Psychiatry and Mental health

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Expanding the spectrum of genes responsible for hereditary motor neuropathies. / 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.

In: Journal of Neurology, Neurosurgery and Psychiatry, 01.01.2019.

Research output: Contribution to journalArticle

Previtali, SC, Zhao, E, Lazarevic, D, Pipitone, GB, Fabrizi, GM, 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, MM, Comi, G, Carrera, P, Devoto, M & Bolino, A 2019, 'Expanding the spectrum of genes responsible for hereditary motor neuropathies', Journal of Neurology, Neurosurgery and Psychiatry. https://doi.org/10.1136/jnnp-2019-320717
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. / Expanding the spectrum of genes responsible for hereditary motor neuropathies. In: Journal of Neurology, Neurosurgery and Psychiatry. 2019.
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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.",
author = "Previtali, {Stefano C.} and Edward Zhao and Dejan Lazarevic and Pipitone, {Giovanni Battista} and Fabrizi, {Gian Maria} and Fiore Manganelli and Anna Mazzeo and Davide Pareyson and Angelo Schenone and Franco Taroni and Giuseppe Vita and Emilia Bellone and Moreno Ferrarini and Matteo Garibaldi and Stefania Magri and Luca Padua and Elena Pennisi and Chiara Pisciotta and Nilo Riva and Vidmer Scaioli and Marina Scarlato and Stefano Tozza and Alessandro Geroldi and Albena Jordanova and Maurizio Ferrari and Ivan Molineris and Reilly, {Mary M.} and Giancarlo Comi and Paola Carrera and Marcella Devoto and Alessandra Bolino",
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T1 - Expanding the spectrum of genes responsible for hereditary motor neuropathies

AU - Previtali, Stefano C.

AU - Zhao, Edward

AU - Lazarevic, Dejan

AU - Pipitone, Giovanni Battista

AU - Fabrizi, Gian Maria

AU - Manganelli, Fiore

AU - Mazzeo, Anna

AU - Pareyson, Davide

AU - Schenone, Angelo

AU - Taroni, Franco

AU - Vita, Giuseppe

AU - Bellone, Emilia

AU - Ferrarini, Moreno

AU - Garibaldi, Matteo

AU - Magri, Stefania

AU - Padua, Luca

AU - Pennisi, Elena

AU - Pisciotta, Chiara

AU - Riva, Nilo

AU - Scaioli, Vidmer

AU - Scarlato, Marina

AU - Tozza, Stefano

AU - Geroldi, Alessandro

AU - Jordanova, Albena

AU - Ferrari, Maurizio

AU - Molineris, Ivan

AU - Reilly, Mary M.

AU - Comi, Giancarlo

AU - Carrera, Paola

AU - Devoto, Marcella

AU - Bolino, Alessandra

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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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