Na channel variants in patients with painful and nonpainful peripheral neuropathy.

OBJECTIVE

To examine the incidence of nonsynonymous missense variants in (Na1.7), (Na1.8), and (Na1.9) 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 (), 31 (), and 15 () 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 haplotype frequencies, between PNRR patients with painful or nonpainful peripheral neuropathy. PNRR patient and missense variant allele frequencies were not significantly different from the Exome Variant Server, European American (EVS-EA) reference population. For , 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 Na1.7 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.