Expanding the spectrum of genes responsible for hereditary motor neuropathies
- 5 June 2019
- journal article
- research article
- Published by BMJ in Journal of Neurology, Neurosurgery & Psychiatry
- Vol. 90 (10), 1171-1179
- https://doi.org/10.1136/jnnp-2019-320717
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.Keywords
Funding Information
- Ministero della Salute (CoFin Regione Lombardia (n. 96), RF-2011-02347127)
This publication has 42 references indexed in Scilit:
- New developments in Charcot–Marie–Tooth neuropathy and related diseasesCurrent Opinion in Neurology, 2017
- A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathyNeurology, 2015
- A practical approach to the genetic neuropathiesPractical Neurology, 2015
- A novel mutation in VCP causes Charcot–Marie–Tooth Type 2 diseaseBrain, 2014
- Exome Sequencing Identifies a REEP1 Mutation Involved in Distal Hereditary Motor Neuropathy Type VAmerican Journal of Human Genetics, 2012
- Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2CNature Genetics, 2009
- Deleterious Variants of FIG4, a Phosphoinositide Phosphatase, in Patients with ALSAmerican Journal of Human Genetics, 2009
- Mutations in dynamin 2 cause dominant centronuclear myopathyNature Genetics, 2005
- Dominant LMNA mutations can cause combined muscular dystrophy and peripheral neuropathyJournal of Neurology, Neurosurgery & Psychiatry, 2005
- Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth diseaseNature Genetics, 2005