{
  "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 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.",
  "abstract_shown": true,
  "affiliations": [
    "Anaesthesia, Pain, and Critical Care Sciences, School of Physiology, Pharmacology, & Neuroscience, University of Bristol, Bristol BS8 1TD, UK.",
    "Newton Research, Kirkwall KW15 1JQ, UK.",
    "Eli Lilly & Company, Bracknell RG12 1PU, UK.",
    "Grünenthal GmbH, Aachen 502099, Germany."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Graeme W T Newton",
      "orcid": "0000-0003-4924-0112"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Corin Charman"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Aidan P Nickerson"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Keith G Phillips"
    },
    {
      "affs": [
        2
      ],
      "name": "Achim Kless"
    },
    {
      "affs": [
        0
      ],
      "name": "James P Dunham"
    },
    {
      "affs": [
        0
      ],
      "name": "Anthony E Pickering",
      "orcid": "0000-0003-0345-0456"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3ytn1aynh0381.bib",
  "cited_by": 0,
  "doi": "10.1093/braincomms/fcag374",
  "fulltext_url": "https://europepmc.org/articles/PMC13684400",
  "id": "3ytn1aynh0381",
  "issns": [
    "2632-1297"
  ],
  "landing_url": "https://europepmc.org/article/MED/42909906",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Ion channel regulation and function"
    ]
  ],
  "openalex": "W7213489454",
  "pdf_url": "https://europepmc.org/articles/PMC13684400?pdf=render",
  "pmcid": "PMC13684400",
  "pmid": "42909906",
  "published": "2026-10-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/3ytn1aynh0381.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:10Z",
      "native_id": "MED:42909906",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42909906"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Ion channel regulation and function",
      "subfield": "molecular-biology"
    }
  ],
  "title": "NaV1.7, 1.8 and 1.9 mutations linked to painful channelopathies have no pain phenotype in UK Biobank.",
  "title_text": "NaV1.7, 1.8 and 1.9 mutations linked to painful channelopathies have no pain phenotype in UK Biobank.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:10Z",
  "url": "https://research.draconitic.com/paper/3ytn1aynh0381",
  "venue": "Brain communications",
  "versions": []
}