Sequencing of Charcot–Marie–Tooth disease genes in a toxic polyneuropathy

Andreas S. Beutler, Amit A. Kulkarni, Rahul Kanwar, Christopher J. Klein, Terry M. Therneau, Rui Qin, Michaela S. Banck, Ganesh K. Boora, Kathryn J. Ruddy, Yanhong Wu, Regenia L. Smalley, Julie M. Cunningham, Nguyet Anh Le‐Lindqwister, Peter Beyerlein, Gary P. Schroth, Anthony J. Windebank, Stephan Züchner, Charles L. Loprinzi

Objective: Mutations 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 polyneuropathy-considered "acquired" in medical parlance-is unknown. Chemotherapy induced peripheral neuropathy (CIPN) occurs commonly in cancer patients and is individually unpredictable. We used CIPN as clinical model to investigate the association of non-CMT polyneuropathy with CMT genes. Methods: 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. 49 CMT genes were analyzed by targeted massively parallel sequencing of genomic DNA from patient blood. Results: 119 (of 269) patients were identified from the two 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=8x10(-3) ). Genetic variation in another CMT gene, ARHGEF10, was highly significantly associated with CIPN (p=5x10(-4) ). Three non-synonymous recurrent single nucleotide variants contributed to the ARHGEF10 signal: rs9657362, rs2294039, and rs17683288. Of these, rs9657362 had the strongest effect (odds ratio of 4.8, p=4x10(-4) ). Interpretation: The 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 co-determined 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. © 2014 American Neurological Association.