Does genotype determine phenotype?

Abstract

The field of epilepsy genetics has made huge leaps in the last decade and now forms part of the clinician's diagnostic armamentarium. The gene with the greatest clinical import to date is undoubtedly SCN1A , which encodes the α1 subunit of the neuronal sodium channel. Mutations were first identified in this pore-forming subunit gene in genetic epilepsy with febrile seizures plus (GEFS+).1 This followed the initial discovery of mutations in a sodium channel auxiliary subunit gene SCN1B , encoding the β1 subunit, in GEFS+.2 GEFS+ is a familial epilepsy syndrome with a spectrum of characteristic yet heterogeneous phenotypes with febrile seizures followed by patterns of generalized and sometimes focal seizures. While generally a benign disorder, the GEFS+ spectrum encompasses epileptic encephalopathies including epilepsy with myoclonic-atonic seizures and Dravet syndrome (DS).3 DS begins with infantile onset of febrile hemiclonic status epilepticus and evolves to a pattern of multiple seizure types including focal, myoclonic, absence, and atonic seizures. Development is normal during the first year with subsequent slowing, poor outcome, and intellectual disability in most cases. The predilection to febrile seizures led to mutational analysis of SCN1A in DS in 2001 and, as they say, the rest is history.4 SCN1A is now a diagnostic test for DS, with >70% of patients having mutations detectable by …