title: Genotype phenotype associations across the voltage-gated sodium channel family.
abstract: Mutations in genes encoding voltage-gated sodium channels have emerged as the most clinically relevant genes associated with epilepsy, cardiac conduction defects, skeletal muscle channelopathies and peripheral pain disorders. Geneticists in partnership with neurologists and cardiologists are often asked to comment on the clinical significance of specific mutations. We have reviewed the evidence relating to genotype phenotype associations among the best known voltage-gated sodium channel related disorders. Comparing over 1300 sodium channel mutations in central and peripheral nervous system, heart and muscle, we have identified many similarities in the genetic and clinical characteristics across the voltage-gated sodium channel family. There is evidence, that the level of impairment a specific mutation causes can be anticipated by the underlying physico-chemical property change of that mutation. Across missense mutations those with higher Grantham scores are associated with more severe phenotypes and truncating mutations underlie the most severe phenotypes. Missense mutations are clustered in specific areas and are associated with distinct phenotypes according to their position in the protein. Inherited mutations tend to be less severe than de novo mutations which are usually associated with greater physico-chemical difference. These findings should lead to a better understanding of the clinical significance of specific voltage-gated sodium channel mutations, aiding geneticists and physicians in the interpretation of genetic variants and counselling individuals and their families.
authors.affiliation: The Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Brunklaus
authors.affiliation: The Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK Molecular Diagnostics, West of Scotland Genetic Services, Southern General Hospital, Glasgow, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Ellis
authors.affiliation: The Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK Molecular Diagnostics, West of Scotland Genetic Services, Southern General Hospital, Glasgow, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Reavey
authors.affiliation: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia Sydney Medical School, University of Sydney, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Semsarian
authors.affiliation: The Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK School of Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, UK.
authors.forename: Sameer M
authors.initials: SM
authors.lastname: Zuberi
mesh_terms: D004831:Epilepsies, Myoclonic / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D009154:Mutation / Q000235:genetics; D003294:Seizures, Febrile / Q000235:genetics; D061566:Voltage-Gated Sodium Channels / Q000235:genetics*
chemical_list: D061566:Voltage-Gated Sodium Channels
keywords: SCN1A; SCN2A; SCN4A; SCN5A; SCN9A