J Clin Invest 117(12):3603–3609. The results of three bioinformatics programs show that the novel mutation could damage the function of the protein (Table 1). Yuan JH, Schulman BR, Effraim PR, Sulayman DH, Jacobs DS, Waxman SG. a Family pedigree. All the evidences confirmed that the SCN9A p.Y1958C mutation should be regarded as pathogenic mutation in this family. HHS BMC Med Genet 20. https://doi.org/10.1186/s12881-019-0745-7, Ding JZJ, GUO Y, Zhang Y, Chen Z (2019) Novel mutations in SCN9A occurring with fever-associated seizures or epilepsy. DNA sequencing of the whole coding region revealed a novel heterozygous nucleotide substitution (c.5873A>G) causing a missense mutation (p.Y1958C). have been described in patients with epilepsy. Mutations in the SCN1A gene and epileptic seizures contribute to disease severity in a mouse model of Dravet syndrome, a study reports.. https://doi.org/10.1212/01.wnl.0000230145.73496.a2, CAS  In our study, a novel SCN9A heterozygous mutation (c.5873A>G) causing a missense mutation (p.Y1958C) was discovered. The disease progresses to include other seizure types (myoclonic, partial), and is also associated with progressive cognitive and behavioral deficits. In addition, we found that oxcarbazepine (OXC), one of the antiepileptic drugs targeting VGSCs, caused a significant shift to more negative potential for the activation and inactivation in WT and mutant channels. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. The patient had febrile seizures, idiopathic generalized epilepsy, and generalized spike-wave patterns on EEG. Regrettably, the mutation didn’t occur in the 4 and the exact cellular mechanism is unclear. Electrophysiological characterization of different SCN9A mutants in HEK293T cells, the previously-reported N641Y and K655R variants, as well as the newly-found W1150R variant, revealed that the current density of the W1150R and N641Y variants was significantly larger than that of the wild-type (WT) channel. Identifying the genetic cause of a patient’s epilepsy can help determine which treatments are likely to … All the seizures last for about 1–2 min and could remit spontaneously. Genotype phenotype associations across the voltage-gated sodium channel family. Several genes have been announced to be associated with GEFS+, in which GABRG2, SCN1A, and GABRA1 account for the major part [6,7,8], while SCN9A is only reported in a few cases. Author summary Epilepsy is defined as a tendency to have seizures, affecting around 1:100 people worldwide. Genetic defects in the coding sequence lead to generalized epilepsy with febrile seizures plus (GEFS +) and a range of childhood epileptic encephalopathies of varied severity (e.g., SMEI). High-throughput sequencing was performed by Illumina NOVASeq 6000 series sequencer; the sequencing process was performed by Beijing Chigene Translational Medicine Research Center. Coding variants of SCN2A, SCN8A, and SCN9A have also been identified in patients with seizures, ataxia, and sensitivity to pain, He presented the first seizure at 1 year and 4 months when encountering a respiratory tract infection with a fever (41 °C). A few of pathogenic SCN9A mutations with or without SCN1A mutations have been identified in epileptic patients. So, we speculate that the SCN9A Y1958C mutation might also affect the selectivity of the ion channel. In affected members of a large Utah family with generalized epilepsy with febrile seizures plus, type 7 (GEFSP7; 613863), Singh et al. 2020 Nov 25;10(12):907. doi: 10.3390/brainsci10120907. This site needs JavaScript to work properly. The variant was compared against publicly available databases such as the 1000 Genomes Project and the Exome Aggregation Consortium database (ExAC). W1150R mutation affects the α-helix of the S1 segment in domain III. In our study, the proband experienced FS and FS+ with absence while his father and aunt only had febrile seizures, probably due to the incomplete penetrance and/or the phenotypic heterogeneity. Despite these recent efforts, the electrophysiological basis of SCN9A mutations remains unclear. Please know we want to keep talking to you about epilepsy, seizures, and what you need. 1b). One of these patients also had an SCN1A variant, which was also detected in a patient with AD febrile seizures. Informed consent was obtained from all individual participants included in the study. PubMed  Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review. Neurol Sci 41, 1913–1917 (2020). Weiterhin wird dieser Natriumkanal in glatten Muskelzellen des Bronchialsystems sowie in Pulmonal- und Koronararterien exprimiert. Some genetic types of epilepsy can be diagnosed using a test that examines genes that have previously been shown to cause epilepsy when affected by genetic alterations. Neurology 89(12):1210–1219. Brunklaus A, Ellis R, Reavey E, Semsarian C, Zuberi SM. https://doi.org/10.1038/gim.2015.30, Article  Correspondence to Furthermore, in all published studies of PE, PEPD and CIP, an increased incidence of seizures is not reported in patients with SCN9A mutations –. SCN9A Epileptic Encephalopathy Mutations Display a Gain-of-function Phenotype and Distinct Sensitivity to Oxcarbazepine August 2019 Neuroscience Bulletin 36(470–482) All published mutations are collated. Part of Springer Nature. b Identification of a heterozygous mutation c.5873A>G (p.Y1958C) in the family members: proband (IV1), proband’s father (III3), proband’s aunt (III1), and proband’s grandmother (II4). Background: Inherited and de novo mutations in sodium channel genes underlie a variety of channelopathies. This mutation (c.5873A>G chr2:167055243 p.Y1958C) occurs in the population at a frequency of < 0.5% in the ExAC database (http://exac.broadinstitute.org/variant/2-167055243-T-C) and has not been reported in previous study or presented in dbSNP (http://evs.gs.washington.edu/EVS/) and 1000 Genomes Project (https://www.internationalgenome.org/). Phenotypes of SCN9A mutations include febrile seizures (FS), genetic epilepsy with febrile seizures plus (GEFS+), and Dravet syndrome (DS), which pose challenges in clinical treatment. eCollection 2020 Jul-Aug. Mol Pain. A different heterozygous SCN9A mutation in the same region (K655R; 603415.0019) was found in an unrelated patient with GEFSP7. https://doi.org/10.1212/WNL.0000000000003087, Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Comm ALQA (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. These conditions include simple febrile (fever-associated) seizures, which start in infancy and usually stop by age 5, and febrile seizures plus (FS+). The proband’s grandmother (II4) and grandfather (II3) did not remember whether they had convulsions in their childhood. Here, we performed a genetic screen of patients with febrile seizures and identified a novel missense mutation of SCN9A (W1150R). In 2019, a heterozygous mutation in the SCN9A gene, p.(Lys655Arg), in two sisters from a non-consanguineous family who presented GEFS+ was detected [11]. © 2021 Springer Nature Switzerland AG. Then, a genome analysis tool kit (GATK version 3.4.0) was used to refine the alignments by performing local indel realignment and subsequent base quality recalibration. 2019). Here, we performed a genetic screen of patients with febrile seizures and identified a novel missense mutation of SCN9A (W1150R). PolyPhen‐2 prediction of pathogenicity for SCN9A mutations associated with the pain disorders erythromelalgia/primary erythermalgia (IEM) and paroxysmal extreme pain disorder (PEPD) is consistent with their established status as causative with 77% and 100% concordance, respectively (Table 2). Electrophysiological function; Epilepsy; Oxcarbazepine; SCN9A; Sensitivity; Voltage-gated sodium channel. We want to stay connected with you. He is diagnosed with epilepsy but not Dravet because he doesn't fit the profile. The patients and his families provided informed consent, and the study was approved by the ethical committees of the First Affiliated Hospital of USTC, Anhui Provincial Hospital. Topic: Parents & Caregivers. Abstract. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Phenotypic heterogeneity [ 10 ] focal seizures [ 11 ] cognitive and behavioral deficits which targets 39Mb region..., electroencephalogram monitoring showed atypical spike-and-slow waves in the right temporal regions sleep... 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