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. 2024 Jun 21;25(13):6832.
doi: 10.3390/ijms25136832.

Genetic Analysis of SCN11A, SCN10A, and SCN9A in Familial Episodic Pain Syndrome (FEPS) in Japan and Proposal of Clinical Diagnostic Criteria

Atsuko Noguchi  1 , Tohru Tezuka  2   3 , Hiroko Okuda  2   4 , Hatasu Kobayashi  5 , Kouji H Harada  6 , Takeshi Yoshida  7 , Shinji Akioka  8 , Keiko Wada  9 , Aya Takeya  2   10 , Risako Kabata-Murasawa  11 , Daiki Kondo  12 , Ken Ishikawa  13 , Takeshi Asano  14 , Michimasa Fujiwara  15 , Nozomi Hishikawa  16 , Tomoyuki Mizukami  17 , Toshiaki Hitomi  4 , Shohab Youssefian  2   18 , Yoshihiro Nagai  19 , Manabu Tanaka  20 , Kaoru Eto  21 , Hideaki Shiraishi  22 , Fumimasa Amaya  19 , Akio Koizumi  2   23 , Tsutomu Takahashi  1
Affiliations

Genetic Analysis of SCN11A, SCN10A, and SCN9A in Familial Episodic Pain Syndrome (FEPS) in Japan and Proposal of Clinical Diagnostic Criteria

Atsuko Noguchi et al. Int J Mol Sci. .

Abstract

Familial episodic pain syndrome (FEPS) is an early childhood onset disorder of severe episodic limb pain caused mainly by pathogenic variants of SCN11A, SCN10A, and SCN9A, which encode three voltage-gated sodium channels (VGSCs) expressed as key determinants of nociceptor excitability in primary sensory neurons. There may still be many undiagnosed patients with FEPS. A better understanding of the associated pathogenesis, epidemiology, and clinical characteristics is needed to provide appropriate diagnosis and care. For this study, nationwide recruitment of Japanese patients was conducted using provisional clinical diagnostic criteria, followed by genetic testing for SCN11A, SCN10A, and SCN9A. In the cohort of 212 recruited patients, genetic testing revealed that 64 patients (30.2%) harbored pathogenic or likely pathogenic variants of these genes, consisting of 42 (19.8%), 14 (6.60%), and 8 (3.77%) patients with variants of SCN11A, SCN10A, and SCN9A, respectively. Meanwhile, the proportions of patients meeting the tentative clinical criteria were 89.1%, 52.0%, and 54.5% among patients with pathogenic or likely pathogenic variants of each of the three genes, suggesting the validity of these clinical criteria, especially for patients with SCN11A variants. These clinical diagnostic criteria of FEPS will accelerate the recruitment of patients with underlying pathogenic variants who are unexpectedly prevalent in Japan.

Keywords: SCN10A; SCN11A; SCN9A; familial episodic pain syndrome.

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Conflict of interest statement

The authors declare the following conflicts of interest: Akio Koizumi, Hiroko Okuda, Tohru Tezuka, and Aya Takeya received personal fees from AlphaNavi Pharma during the study period. Hiroko Okuda and Tohru Tezuka received grants from AlphaNavi Pharma during the study period. Shohab Youssefian received funding from AlphaNavi Pharma. Atsuko Noguchi, Takeshi Yoshida, Shinji Akioka, Takeshi Asano, Michimasa Fujiwara, Manabu Tanaka, Kaoru Eto, Hideaki Shiraishi, and Tsutomu Takahashi received trial compensation from Alpha Navi Pharma. Atsuko Noguchi, Tsutomu Takahashi, Akio Koizumi, Hatasu Kobayashi, and Kouji H. Harada have a patent regarding SCN11A (name of patent, “Pain gene and its applications”; Japanese Patent Application No. P2016-098215A).

Figures

Figure 1
Figure 1
FEPS patients analyzed for variants of SCN11A, SCN10A, and SCN9A. The figure shows an overview of the study cohort. A total of 213 individuals were recruited, with one individual excluded under the diagnosis of Fabry’s disease. Screening for variants of three VGSCs (SCN11A, SCN10A, and SCN9A) was conducted for the remaining 212 individuals, revealing variants in 82 individuals. Among them, 42 individuals (19.8%) had pathogenic or likely pathogenic variants of SCN11A, 14 individuals (6.6%) had variants of SCN10A, and 8 individuals (3.77%) had variants of SCN9A.
Figure 2
Figure 2
Genetic variants of SCN11A, SCN10A, and SCN9A identified in this study and their location in the Nav1.9, Nav1.8, and Nav1.7. Nav1.9, Nav1.8, and Nav1.7 have four domains (DI~DIV), each of which consistent of six transmembrane segments. Genetic variants are shown in schematic diagrams for Nav1.9 (a), 1,8 (b), and 1.7 (c), respectively. The color of each variant indicates its rating, based on the American College of Medical Genetics and Genomics standards and guidelines for interpreting sequence variants. Red represents “pathogenic,” purple represents “likely pathogenic,” green represents “likely benign,” and light blue represents “VUS”.
Figure 2
Figure 2
Genetic variants of SCN11A, SCN10A, and SCN9A identified in this study and their location in the Nav1.9, Nav1.8, and Nav1.7. Nav1.9, Nav1.8, and Nav1.7 have four domains (DI~DIV), each of which consistent of six transmembrane segments. Genetic variants are shown in schematic diagrams for Nav1.9 (a), 1,8 (b), and 1.7 (c), respectively. The color of each variant indicates its rating, based on the American College of Medical Genetics and Genomics standards and guidelines for interpreting sequence variants. Red represents “pathogenic,” purple represents “likely pathogenic,” green represents “likely benign,” and light blue represents “VUS”.
Figure 3
Figure 3
Onset age of pain attacks in FEPS patients with pathogenic or likely pathogenic variants of SCN11A, SCN10A, or SCN9A. The blue column indicates SCN11A, the yellow column indicates SCN10A, and the green column indicates SCN9A.
See this image and copyright information in PMC

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