The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype

Human Mutation
Heng MengWei-Ping Liao

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 t...Continue Reading

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Citations

Apr 29, 2016·Neurology. Genetics·Xiao-Rong LiuWei-Ping Liao
Jul 29, 2016·Molecular Genetics & Genomic Medicine·Tania DjémiéUNKNOWN EuroEPINOMICS‐RES Dravet working group
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