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The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We enrolled eight patients presenting with early\u2010onset painful peripheral neuropathies, consisting of six cases exhibiting EM\/EM\u2010like disorders and two cases clinically diagnosed with PEPD. We conducted a gene\u2010panel sequencing targeting 18 genes associated with hereditary sensory and\/or autonomic neuropathy. We introduced novel <jats:italic>SCN9A<\/jats:italic> mutation (F1624S) into a GFP\u20102A\u2010Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild\u2010type and F1624S Nav1.7 channels using an automated high\u2010throughput patch\u2010clamp system.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>From two patients displaying EM\u2010like\/EM phenotypes, we identified two <jats:italic>SCN9A<\/jats:italic> mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in <jats:italic>SCN9A<\/jats:italic>, F1624S (novel) and A1632E. Patch\u2010clamp analysis of Nav1.7\u2010F1624S revealed depolarizing shifts in both steady\u2010state fast inactivation (17.4\u2009mV, <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001) and slow inactivation (5.5\u2009mV, <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001), but no effect on channel activation was observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Clinical features observed in our patients broaden the phenotypic spectrum of <jats:italic>SCN9A<\/jats:italic>\u2010related pain disorders, and the electrophysiological analysis enriches the understanding of genotype\u2013phenotype association caused by Nav1.7 gain\u2010of\u2010function mutations.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jns.12590","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T14:26:56Z","timestamp":1691591216000},"page":"597-607","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Genetic, electrophysiological, and pathological studies on patients with <scp><i>SCN9A<\/i><\/scp>\u2010related pain disorders"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3808-7813","authenticated-orcid":false,"given":"Jun\u2010Hui","family":"Yuan","sequence":"first","affiliation":[{"name":"Department of Neurology and Geriatrics Kagoshima University Graduate School of Medical and Dental Sciences  Kagoshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Neurology Yale School of Medicine  New Haven Connecticut 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