The two faces of SCN1A. Even though the range of phenotypes associated with mutations in SCN1A can be conceptualized as a continuum, there are usually two distinct entities in clinical practice: the severe, epileptic encephalopathy of Dravet Syndrome due to de novo mutations and the usually mild fever-related epilepsies in autosomal dominant GEFS+ families. While Dravet Syndrome can also be seen in some families with Genetic Epilepsy with Febrile Seizures Plus (GEFS+), this is a rare phenomenon; there is usually little overlap between Dravet Syndrome and GEFS+. Within the Israel Epilepsy Family Project, we came across such a family with overlapping phenotypes. This recently published large GEFS+ family probably has the widest phenotypic range reported to date.
Epilepsy, genes and fever. Febrile Seizures are the most common convulsive event in humans. Up to 5% of children between the age of 6 months and 6 years have Febrile Seizures. Twin studies point towards a strong genetic basis, and FS are frequently seen in families. Despite this, there is not a single gene known for Febrile Seizures. All our knowledge regarding the genetics of fever-related epilepsies comes from GEFS+. While the “FS” in GEFS+ stands for Febrile Seizures, both conditions must not be confused. The core phenotype in GEFS+ families are Febrile Seizures Plus. This epilepsy syndrome refers to FS persisting beyond the age of 6 years or FS in conjunction with other, afebrile seizure types. This distinction may seem like minutia, but the difference between simple FS and FS+ is crucial. It was only through careful phenotyping of GEFS+ families that the first genes for fever-related epilepsies including SCN1A, SCN1B, and GABRG2 could be discovered. Twin studies suggest that FS and FS+ are two distinct entities. And with respect to the genetics of simple FS, we are still looking and there is no gene in sight.
Extremes. The story gets more complex, as simple FS can also occur in GEFS+ families. In fact, simple FS are the most common phenotype in these families. However, the overall gestalt of the familial phenotypes usually reveals the GEFS+ character of the familial disease. But how extreme can the distribution of phenotypes within a GEFS+ family be? Large families are the only way of answering this question. Within the Israel Epilepsy Family Project, we recruited a large GEFS+ family with a novel SCN1A mutation. This family was comprised of 14 affected and 3 unaffected individuals, with a penetrance of ~80%, which is in line with the literature. However, there were two surprising findings about this family. First, the phenotypic range was extreme. SCN1A in this family was associated with Dravet Syndrome as well as unaffected carriers. Secondly, the unaffected carriers all presented within a single sibship.
The whole story. The pedigree of this large Israeli family already suggests that SCN1A is not the full story in this family. The SCN1A mutation in the proband affected with Dravet Syndrome may still be considered causative. However, the family pattern clearly suggests that there must be something else going on. The size of the family makes it possible for us to appreciate the range of phenotypes that can be associated with this mutation. There is some evidence in this family that phenotype severity of SCN1A carriers has some other familial causes, given that phenotype severity in this family is not randomly distributed. Applying whole exome or genome sequencing approaches in families like this may help us find potential modifiers.
Relevance for EuroEPINOMICS. The phenotypes of SCN1A in GEFS+ are variable, but the source of this variability is unknown. Families with an extreme phenotype distribution may help to investigate the role of additional genetic or non-genetic risk factors. SCN9A variants were recently suggested as modifiers of Dravet Syndrome. Assessing candidates like this may help pinpoint the mechanisms that determine the severity of the GEFS+ phenotypes in families. Also, this might help identify novel mechanisms that can be affected through antiepileptic drugs. Either way, the overall phenotype in this family demonstrates that referring to GEFS+ as an autosomal dominant epilepsy underestimates the complexity of the phenotypes.
Israel Epilepsy Family Project. This year, we invite the community of Young Researchers to Sde Boker in Israel, the current home of the Israel Epilepsy Family Project. There is an ongoing need for family studies in the field of epilepsy genetics. Family studies have a strong advantage, especially when the range of phenotypes associated with a given gene need to be delineated. In the same way as seen in epileptic encephalopathies, familial epilepsies will show a strong degree of genetic heterogeneity. Therefore, performing large-scale family studies are possibly the only way of generating sufficient evidence for a certain gene by identifying a second family with alterations in the same genes. With respect to the Israel Epilepsy Family Project, I am happy to announce that we finally made it into the second round of a Trilateral Grant, a particular trilateral funding mechanism for scientific projects connecting Germany, Israel, and Palestine. Keep your fingers crossed in Spring 2014 for the full proposal!