NaV1.7, 1.8 and 1.9 mutations linked to painful channelopathies have no pain phenotype in UK Biobank

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ID: 331632
2026
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Abstract
Abstract The voltage-gated sodium channels NaV1.7, NaV1.8, and NaV1.9, encoded by the SCN9A, SCN10A, and SCN11A genes, respectively, are integral to nociceptor excitability and pain sensation. Multiple gain-of-function mutations in these ion channels have been reported to cause autosomal dominant painful channelopathies, including primary erythromelalgia, paroxysmal extreme pain disorder, and familial episodic pain. Conversely, autosomal recessive loss-of-function mutations in NaV1.7 have been reported to cause painless channelopathies. The prevalence and impact on carriers of these voltage-gated sodium channel genetic variants in the wider population has yet to be explored. A combined genetic database and literature search was performed to identify pathogenic gain-of-function variants linked to painful channelopathies which had supporting in vitro electrophysiological evidence. Loss-of-function variants were identified by their inferred impact upon protein sequence. We investigated these variants within the UK Biobank cohort 500k whole-exome sequencing dataset. Logistic regression was used to examine whether carrying these variants was associated with chronic pain, neuropathic pain, and analgesic or anti-neuropathic drug prescription (adjusting for age, sex, and 10 genetic principal components). For NaV1.7, 20/59 putative pathogenic gain-of-function mutations identified from literature were found in UK Biobank, with 148,901 carriers (>29% of the cohort). For NaV1.8, 4/5 gain-of-function mutations were found, with 1,104 carriers. For NaV1.9, 13/17 gain-of-function mutations were found, with 1,324 carriers. For predicted loss-of-function mutations in NaV1.7, NaV1.8, and NaV1.9, there were 723, 1,307, and 1,143 heterozygous carriers, respectively, and 2 homozygous NaV1.9 loss-of-function carriers. A total of 21 NaV mutation groups had ≥50 heterozygous carriers allowing logistic regression analysis. None of these groups had a significantly altered risk of chronic or neuropathic pain. Similarly, no differences in prescriptions of opioid analgesics or anti-neuropathic pain medications were found. Subsequent pathogenicity prediction indicated that the gain-of-function variants called in UK Biobank had significantly lower predicted pathogenicity scores than those that were absent from the cohort. These findings show that over one third of the previously reported pathogenic NaV1.7 gain-of-function mutations are likely to be benign for pain. This study challenges the previously assumed high penetrance of these NaV gain-of-function mutations for chronic pain, and we make recommendations to optimise the evidence-based criteria for genetic association studies investigating the role of ion channel variants in the pathogenesis of pain.
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Authors Graeme W. T. Newton, Corin Charman, Aidan P. Nickerson, Keith Geoffrey Phillips, Achim Kless, Jim Dunham, Anthony E Pickering
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Journal Brain communications
Year 2026
DOI
10.1093/braincomms/fcag374
URL
https://doi.org/10.1093/braincomms/fcag374
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