Update. As information on the epilepsies caused by SCN1A mutations are amongst our most frequently read posts, we thought that a quick update on the state-of-the art regarding SCN1A would be timely. These are the ten things about SCN1A that you should known in 2014.
1 – GEFS+ and Dravet Syndrome. There has been little change to the central dogma of SCN1A-related epilepsy in 2014: mutations in SCN1A are the cause of two epilepsy syndromes, namely the severe epilepsy of Dravet Syndrome and the mild familial epilepsy syndrome of Genetic/Generalized Epilepsy with Febrile Seizures Plus (GEFS+). Dravet Syndrome is a devastating childhood epilepsy with prominent fever-associated seizures. GEFS+ is a milder autosomal dominant familial epilepsy syndrome. The GEFS+ phenotypes span a broad range from unaffected carriers, simple Febrile Seizures, Febrile Seizures Plus, and sometimes more severe epilepsies.
2 – Phenotype prediction of SCN1A mutations. There is some correlation between the type of the mutation and the resulting phenotype. For example, a mutation that disrupts the SCN1A protein is more likely to be found in patients with Dravet Syndrome than in patients with GEFS+. However, prediction of the phenotype based on the type of mutation is not possible, as patients with the same mutations can have a broad range of phenotypes. SCN1A testing in 2014 remains diagnostic, not predictive.
3 – SCN1A more common. Various studies using next-generation sequencing find hidden SCN1A mutations also in patients that were previously considered SCN1A mutation negative. This observation suggests that the Dravet Syndrome phenotype is tightly linked to SCN1A and that a negative mutation finding in a patient with classical Dravet Syndrome is probably more likely to be false negative than due to a different gene. To put this differently: if you have a patient with typical Dravet Syndrome and a negative test for SCN1A with classical sequencing, you are probably more likely to find a hidden SCN1A mutation on re-testing than finding a mutation in a different gene. Data is currently coming together, which will reveal whether this relatively bold assumption is true.
4 – Novel genes. Despite the unexpected re-discovery of SCN1A mutations, there are additional genes for Dravet Syndrome that were discovered during the last 12 months. These include CHD2, GABRA1, STXBP1, and HCN1. The hyperlinks will take you to our blog posts about these genes.
5 – Modifier genes not ready for prime time. There are various studies on modifier genes of SCN1A. In a nutshell, none of these studies is sufficiently replicated to securely implicate a modifier gene. Sufficiently powered studies, however, will hopefully be possible in the near future with increasing numbers of patients.
6 – Meet the neighbors – SCN2A, SCN8A, SCN9A. The SCN1A gene is part of gene cluster on chromosome 2 that probably arose through gene duplication. The SCN2A and SCN8A gene have also been implicated as a cause of severe childhood epilepsies in the last 12 months. The SCN9A gene, known to cause erythermalgia, a hereditary pain disorder, was suggested as a modifier gene, but the data is not sufficiently solid at the moment (see above).
7 – A general susceptibility gene. Two association studies have suggested common variants in SCN1A as risk factors for Idiopathic/Genetic Generalized Epilepsies (IGE/GGE) and Temporal Lobe Epilepsy. While these studies demonstrate that SCN1A variants contribute to human epilepsies across a wide spectrum of risk factors, these association studies usually have little clinical impact. The increase in risk is too small to be used in clinical setting for counseling or treatment decisions.
8 – Personalized medicine. Using high-throughput compound screening, clemizole was identified as a substance that reduces seizures and EEG activity in a zebrafish model of Dravet Syndrome. Future studies will show whether this finding is robust and can be translated to clinical trials.
9 – SCN1A in exome databases. The availability of large-scale genetic datasets raises the question whether disruptive mutations in SCN1A can also be identified in controls. A single severe SCN1A mutation can be found in the >6000 exomes of the Exome Variant Server. This finding highlights many of the current issues of large-scale genomic including possible sequencing artifacts, lack of phenotypic data, and the question of whether population genetic data may make us question our concept of monogenic disorders.
10 – Other phenotypes – De novo mutations in SCN1A are occasionally identified in other severe childhood epilepsies including Myoclonic Astatic Epilepsy (MAE), Lennox-Gastaut Syndrome, and Migrating Partial Epilepsy of Infancy (MMPSI). These findings, however, are too rare to produce a coherent picture of additional SCN1A-related epilepsies. The take-home message is that other phenotypes can also be the consequence of an underlying SCN1A mutation.