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

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 prescriptions (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 1104 carriers. For NaV1.9, 13/17 gain-of-function mutations were found, with 1324 carriers. For predicted loss-of-function mutations in NaV1.7, NaV1.8 and NaV1.9, there were 723, 1307 and 1143 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 optimize the evidence-based criteria for genetic association studies investigating the role of ion channel variants in the pathogenesis of pain.