title: The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype.
abstract: Mutations in the SCN1A gene have been identified in epilepsy patients with widely variable phenotypes and modes of inheritance and in asymptomatic carriers. This raises challenges in evaluating the pathogenicity of SCN1A mutations. We systematically reviewed all SCN1A mutations and established a database containing information on functional alterations. In total, 1,257 mutations have been identified, of which 81.8% were not recurrent. There was a negative correlation between phenotype severity and missense mutation frequency. Further analyses suggested close relationships among genotype, functional alteration, and phenotype. Missense mutations located in different sodium channel regions were associated with distinct functional changes. Missense mutations in the pore region were characterized by the complete loss of function, similar to haploinsufficiency. Mutations with severe phenotypes were more frequently located in the pore region, suggesting that functional alterations are critical in evaluating pathogenicity and can be applied to patient management. A negative correlation was found between phenotype severity and familial incidence, and incomplete penetrance was associated with missense and splice site mutations, but not truncations or genomic rearrangements, suggesting clinical genetic counseling applications. Mosaic mutations with a load of 12.5-25.0% were potentially pathogenic with low penetrance, suggesting the need for future studies on less pathogenic genomic variations.
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.|Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Meng
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
authors.forename: Hai-Qing
authors.initials: HQ
authors.lastname: Xu
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Yu
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
authors.forename: Guo-Wang
authors.initials: GW
authors.lastname: Lin
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
authors.forename: Na
authors.initials: N
authors.lastname: He
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
authors.forename: Yi-Wu
authors.initials: YW
authors.lastname: Shi
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
authors.forename: Xiao-Rong
authors.initials: XR
authors.lastname: Liu
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Tang
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
authors.forename: Yue-Sheng
authors.initials: YS
authors.lastname: Long
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Yi
authors.affiliation: Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Liao
mesh_terms: D030541:Databases, Genetic; D004827:Epilepsy / Q000235:genetics; D005190:Family; D056726:Genetic Association Studies / Q000379:methods; D005838:Genotype; D006801:Humans; D040582:Inheritance Patterns; D009030:Mosaicism; D009154:Mutation; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human
keywords: SCN1A; epilepsy; mosaicism; pathogenicity; sodium channel Nav1.1