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

doi:10.1002/ana.24265

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

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

Abstract

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 a clinical model to investigate the association of non-CMT polyneuropathy with CMT genes.

Methods: A 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.

Results: A 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 × 10^-3). Genetic variation in another CMT gene, ARHGEF10, was highly significantly associated with CIPN (p=5 × 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 × 10^-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 codetermined by genetic etiological factors, of which some may be related to genes already known to cause the phenotypically related Mendelian disorders of CMT.

Original language	English (US)
Pages (from-to)	727-737
Number of pages	11
Journal	Annals of neurology
Volume	76
Issue number	5
DOIs	https://doi.org/10.1002/ana.24265
State	Published - Nov 1 2014

ASJC Scopus subject areas

Neurology
Clinical Neurology

Access to Document

10.1002/ana.24265

Cite this

Beutler, A. S., Kulkarni, A. A., Kanwar, R., Klein, C. J., Therneau, T. M., Qin, R., Banck, M. S., Boora, G. K., Ruddy, K. J., Wu, Y., Smalley, R. L., Cunningham, J. M., Le-Lindqwister, N. A., Beyerlein, P., Schroth, G. P., Windebank, A. J., Züchner, S., & Loprinzi, C. L. (2014). Sequencing of charcot-marie-tooth disease genes in a toxic polyneuropathy. Annals of neurology, 76(5), 727-737. https://doi.org/10.1002/ana.24265

Beutler, AS, Kulkarni, AA, Kanwar, R, Klein, CJ , Therneau, TM, Qin, R, Banck, MS, Boora, GK, Ruddy, KJ, Wu, Y, Smalley, RL, Cunningham, JM, Le-Lindqwister, NA, Beyerlein, P, Schroth, GP, Windebank, AJ, Züchner, S & Loprinzi, CL 2014, 'Sequencing of charcot-marie-tooth disease genes in a toxic polyneuropathy', Annals of neurology, vol. 76, no. 5, pp. 727-737. https://doi.org/10.1002/ana.24265

@article{983555d7fb754f978a2abfbe73821530,

title = "Sequencing of charcot-marie-tooth disease genes in a toxic polyneuropathy",

abstract = "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 a clinical model to investigate the association of non-CMT polyneuropathy with CMT genes.Methods: A 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.Results: A 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 × 10-3). Genetic variation in another CMT gene, ARHGEF10, was highly significantly associated with CIPN (p=5 × 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 × 10-4).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 codetermined by genetic etiological factors, of which some may be related to genes already known to cause the phenotypically related Mendelian disorders of CMT.",

author = "Beutler, {Andreas S.} and Kulkarni, {Amit A.} and Rahul Kanwar and Klein, {Christopher J.} and Therneau, {Terry M.} and Rui Qin and Banck, {Michaela S.} and Boora, {Ganesh K.} and Ruddy, {Kathryn J.} and Yanhong Wu and Smalley, {Regenia L.} and Cunningham, {Julie M.} and Le-Lindqwister, {Nguyet Anh} and Peter Beyerlein and Schroth, {Gary P.} and Windebank, {Anthony J.} and Stephan Z{\"u}chner and Loprinzi, {Charles L.}",

note = "Publisher Copyright: {\textcopyright} 2014 American Neurological Association.",

year = "2014",

month = nov,

day = "1",

doi = "10.1002/ana.24265",

language = "English (US)",

volume = "76",

pages = "727--737",

journal = "Annals of neurology",

issn = "0364-5134",

publisher = "John Wiley and Sons Inc.",

number = "5",

}

TY - JOUR

T1 - Sequencing of charcot-marie-tooth disease genes in a toxic polyneuropathy

AU - Beutler, Andreas S.

AU - Kulkarni, Amit A.

AU - Kanwar, Rahul

AU - Klein, Christopher J.

AU - Therneau, Terry M.

AU - Qin, Rui

AU - Banck, Michaela S.

AU - Boora, Ganesh K.

AU - Ruddy, Kathryn J.

AU - Wu, Yanhong

AU - Smalley, Regenia L.

AU - Cunningham, Julie M.

AU - Le-Lindqwister, Nguyet Anh

AU - Beyerlein, Peter

AU - Schroth, Gary P.

AU - Windebank, Anthony J.

AU - Züchner, Stephan

AU - Loprinzi, Charles L.

PY - 2014/11/1

Y1 - 2014/11/1

N2 - 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 a clinical model to investigate the association of non-CMT polyneuropathy with CMT genes.Methods: A 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.Results: A 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 × 10-3). Genetic variation in another CMT gene, ARHGEF10, was highly significantly associated with CIPN (p=5 × 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 × 10-4).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 codetermined by genetic etiological factors, of which some may be related to genes already known to cause the phenotypically related Mendelian disorders of CMT.

AB - 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 a clinical model to investigate the association of non-CMT polyneuropathy with CMT genes.Methods: A 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.Results: A 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 × 10-3). Genetic variation in another CMT gene, ARHGEF10, was highly significantly associated with CIPN (p=5 × 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 × 10-4).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 codetermined by genetic etiological factors, of which some may be related to genes already known to cause the phenotypically related Mendelian disorders of CMT.

UR - http://www.scopus.com/inward/record.url?scp=84912102998&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84912102998&partnerID=8YFLogxK

U2 - 10.1002/ana.24265

DO - 10.1002/ana.24265

M3 - Article

C2 - 25164601

AN - SCOPUS:84912102998

SN - 0364-5134

VL - 76

SP - 727

EP - 737

JO - Annals of neurology

JF - Annals of neurology

IS - 5

ER -

Sequencing of charcot-marie-tooth disease genes in a toxic polyneuropathy

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this