NaV channel variants in patients with painful and nonpainful peripheral neuropathy

Samir Wadhawan; Saumya Pant; Ryan Golhar; Stefan Kirov; John Thompson; Leslie Jacobsen; Irfan Qureshi; Senda Ajroud-Driss; Roy Freeman; David M Simpson; A Gordon Smith; Ahmet Hoke; Linda J Bristow

doi:10.1212/NXG.0000000000000207

Na_V channel variants in patients with painful and nonpainful peripheral neuropathy

Neurol Genet. 2017 Dec 15;3(6):e207. doi: 10.1212/NXG.0000000000000207. eCollection 2017 Dec.

Affiliation

¹ Department of Translational Biomarkers and Computational Genomics (S.W., S.P., R.G., S.K., J.T.), Bristol-Myers Squibb, Hopewell Site, Pennington, NJ; Department of Genetically Defined Diseases Discovery Biology (L.J.B.), Bristol-Myers Squibb, Wallingford, CT; Department of Innovative Clinical Development (I.Q., L.J.), Bristol-Myers Squibb, Lawrenceville, Princeton, NJ; Department of Neurology (S.A.-D.), Northwestern Medical Faculty Foundation, Chicago, IL; Department of Neurology (R.F.), Beth Israel Medical Center, Harvard School of Medicine, Boston, MA; Department of Neurology (D.M.S.), Icahn School of Medicine at Mount Sinai Medical Center, New York, NY; Department of Neurology (A.G.S.), University of Utah School of Medicine, Salt Lake City, UT; Department of Neurology (A.H.), Johns Hopkins University, Baltimore, MD. S.P. is currently affiliated with Biocon Bristol-Myers Squibb Research Center, Bangalore, India.

Abstract

Objective: To examine the incidence of nonsynonymous missense variants in SCN9A (Na_V1.7), SCN10A (Na_V1.8), and SCN11A (Na_V1.9) in patients with painful and nonpainful peripheral neuropathy.

Methods: Next-generation sequencing was performed on 457 patient DNA samples provided by the Peripheral Neuropathy Research Registry (PNRR). The patient diagnosis was as follows: 278 idiopathic peripheral neuropathy (67% painful and 33% nonpainful) and 179 diabetic distal polyneuropathy (77% painful and 23% nonpainful).

Results: We identified 36 (SCN9A), 31 (SCN10A), and 15 (SCN11A) nonsynonymous missense variants, with 47.7% of patients carrying a low-frequency (minor allele frequency <5%) missense variant in at least 1 gene. The incidence of previously reported gain-of-function missense variants was low (≤3%), and these were detected in patients with and without pain. There were no significant differences in missense variant allele frequencies of any gene, or SCN9A haplotype frequencies, between PNRR patients with painful or nonpainful peripheral neuropathy. PNRR patient SCN9A and SCN11A missense variant allele frequencies were not significantly different from the Exome Variant Server, European American (EVS-EA) reference population. For SCN10A, there was a significant increase in the alternate allele frequency of the common variant p.V1073A and low-frequency variant pS509P in PNRR patients compared with EVS-EA and the 1000 Genomes European reference populations.

Conclusions: These results suggest that identification of a genetically defined subpopulation for testing of Na_V1.7 inhibitors in patients with peripheral neuropathy is unlikely and that additional factors, beyond expression of previously reported disease "mutations," are more important for the development of painful neuropathy than previously discussed.