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Sequencing of Charcot-Marie-Tooth Disease Genes in a Toxic Polyneuropathy

Sequencing of Charcot-Marie-Tooth Disease Genes in a Toxic Polyneuropathy
ObjectiveMutations in Charcot-Marie-Tooth disease (CMT) genes are the cause of rare familial forms of polyneuropathy. Whether allelic variability in CMT genes is also associated with common forms of polyneuropathyconsidered acquired in medical parlanceis unknown. Chemotherapy-induced peripheral neuropathy (CIPN) occurs commonly in cancer patients and is individually unpredictable. We used CIPN as a clinical model to investigate the association of non-CMT polyneuropathy with CMT genes. MethodsA total of 269 neurologically asymptomatic cancer patients were enrolled in the clinical trial Alliance N08C1 to receive the neurotoxic drug paclitaxel, while undergoing prospective assessments for polyneuropathy. Forty-nine CMT genes were analyzed by targeted massively parallel sequencing of genomic DNA from patient blood. ResultsA total of 119 (of 269) patients were identified from the 2 ends of the polyneuropathy phenotype distribution: patients that were most and least susceptible to paclitaxel polyneuropathy. The CMT gene PRX was found to be deleteriously mutated in patients who were susceptible to CIPN but not in controls (p=8 x 10(-3)). Genetic variation in another CMT gene, ARHGEF10, was highly significantly associated with CIPN (p=5 x 10(-4)). Three nonsynonymous recurrent single nucleotide variants contributed to the ARHGEF10 signal: rs9657362, rs2294039, and rs17683288. Of these, rs9657362 had the strongest effect (odds ratio=4.8, p=4 x 10(-4)). InterpretationThe results reveal an association of CMT gene allelic variability with susceptibility to CIPN. The findings raise the possibility that other acquired polyneuropathies may also be codetermined by genetic etiological factors, of which some may be related to genes already known to cause the phenotypically related Mendelian disorders of CMT. Ann Neurol 2014;76:727-737
Publication type:
Journal article
Annals of Neurology
Document status:
Induced Peripheral Neuropathy; Vincristine Neurotoxicity; Hereditary Motor; Outcome Measures; Mutations; Periaxin; Patient; Conduction; Variants; Update
Beutler, A., Kulkarni, A., Kanwar, R., Klein, C., Therneau, T., Qin, R., et al. (2014). Sequencing of Charcot-Marie-Tooth Disease Genes in a Toxic Polyneuropathy Annals of Neurology. 76 (5), 727-737.
    author           = {Beutler, Andreas S. and Kulkarni, Amit A. and Kanwar, Rahul and Klein, Christopher J. and Therneau, Terry M. and Qin, Rui and Banck, Michaela S. and Boora, Ganesh K. and Ruddy, Kathryn J. and Wu, Yanhong and Smalley, Regenia L. and Cunningham, Julie M. and Le-Lindqwister, Nguyet Anh and Beyerlein, Peter and Schroth, Gary P. and Windebank, Anthony J. and Zuechner, Stephan and Loprinzi, Charles L.},
    title            = {Sequencing of Charcot-Marie-Tooth Disease Genes in a Toxic Polyneuropathy},
    journal          = {Annals of Neurology},
    year             = {2014},
    volume           = {76},
    number           = {5},
    pages            = {727-737},
    doi              = {10.1002/ana.24265},

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