Background & Aims

The voltage-gated sodium channel NaV1.7, encoded by the SCN9A gene, is integral to nociceptor excitability and pain sensation. Loss-of-function SCN9A variants cause congenital insensitivity to pain in an autosomal recessive manner [1]. Multiple gain-of-function SCN9A variants (>50 to date) have been reported to cause autosomal dominant channelopathies, including primary erythromelalgia and paroxysmal extreme pain disorder (PEPD), and they are associated with painful small fibre neuropathies (SFN) [2]. The prevalence and impact on carriers of these high penetrance gain-of-function variants in large population cohorts has yet to be explored.
Aim: To investigate the prevalence of SCN9A rare variants reported to cause gain-of-function channelopathies and assess their association with pain and medication use in the UK BioBank cohort.

Methods

A literature search was performed to identify all pathogenic SCN9A variants reported in primary erythromelalgia and PEPD patients. We also included SCN9A variants that were associated with SFN and familial epilepsy and had gain-of-function in vitro electrophysiological evidence. Carriers of these variants were identified within the UK BioBank (UKB) 470K whole-exome sequencing dataset. Participants who carried >1 pathogenic variant identified from the literature search were excluded from the analysis.
Logistic regression, adjusting for age and sex, was used to examine pathogenic variant carriers for associations with chronic pain (any pain >3 months at recruitment), neuropathic pain (self-reported DN4 ?3 in the Experience of Pain Questionnaire), and analgesic (strong opioid, weak opioid) or anti-neuropathic (gabapentinoid, NaV blocker, tricyclic antidepressant) drug prescription. An FDR-adjusted P value threshold of 0.05 was used, adjusting for the 7 binary phenotypes examined.

Results

59 putative pathogenic gain-of-function variants in SCN9A were identified, of which 20 have heterozygous carriers within the UKB. The 20 variants were associated with SFN (9), primary erythromelalgia (8), epilepsy (2), and PEPD (1). 18/20 variants had electrophysiological gain-of-function confirmed in vitro. We selected 13/20 variants which had >50 heterozygous carriers for logistic regression analysis.
NaV1.7 mutation carriers did not have an increased risk of chronic or neuropathic pain. Additionally, we did not find any increase in prescriptions for opioid analgesics or anti-neuropathic medications. The only exception was related to the familial epilepsy mutation K655R, which was significantly associated with increased NaV blocker prescription. We note that the reported minor allele frequencies (MAF) of these variants in gnomAD are more common than the expected frequency for pathogenicity or the prevalence of their associated diseases (median MAF 0.23%, range = 0.01-2.75%).

Conclusions

There are cumulatively over 150k participants who are heterozygous carriers of SCN9A putative pathogenic mutations in the UKB that have no evidence of an associated pain phenotype or increased prescription of pain medications.
Our findings suggest that many SCN9A variants, previously reported in the literature to be pathogenic, appear more likely to be benign. We conclude that the in vitro gain-of-function does not necessarily translate into nociceptor hyperexcitability that causes pain. We note that we were able to detect an impact of other variants on pain and analgesic consumption within UKB using the same analysis pipeline.
This study challenges the previously assumed high penetrance of SCN9A gain-of-function variants for pain. The targeted sequencing of SCN9A alone to identify candidate pathogenic variants appears to be insufficient for reliably identifying the cause of a monogenic pain phenotype. It has likely resulted in some SCN9A variants being misinterpreted as pathogenic.

References

1. Cox, J. J., et al. (2006). An SCN9A channelopathy causes congenital inability to experience pain. Nature, 444(7121), 894-898.
2. Dib-Hajj, S. D., et al. (2013). The NaV1.7 sodium channel: from molecule to man. Nature Reviews Neuroscience, 14(1), 49-62.

Presenting Author

Anthony E Pickering

Poster Authors

Graeme Newton

PhD

University of Bristol

Lead Author

Anthony Pickering MB ChB

PhD

University of Bristol

Lead Author

James Dunham

University of Bristol, United Kingdom.

Lead Author

Topics

  • Genetics