From unaffected to Dravet Syndrome – extreme SCN1A phenotypes in a large GEFS+ family

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.

Pedigree of the large GEFS+ family with 14 affected and 3 unaffected carriers. The novel missense mutation in exon 21 (p.K1372E) results in a broad range of phenotypes. This range of phenotypes seen in this family suggests that SCN1A is not the entire story. It will be investigate whether the modifying factors are genetic or non-genetic. The pattern of phenotypes suggests some intra-familial factors.

Pedigree of the large GEFS+ family with 14 affected and 3 unaffected carriers. The novel missense mutation in exon 21 (p.K1372E) results in a broad range of phenotypes. This range of phenotypes seen in this family suggests that SCN1A is not the entire story. It will be investigate whether the modifying factors are genetic or non-genetic. The pattern of phenotypes suggests some intra-familial factors.

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!

Ingo Helbig

Child Neurology Fellow and epilepsy genetics researcher at the Children’s Hospital of Philadelphia (CHOP), USA and Department of Neuropediatrics, Kiel, Germany

Facebook Twitter 

15 thoughts on “From unaffected to Dravet Syndrome – extreme SCN1A phenotypes in a large GEFS+ family

  1. Pingback: Infantile Spasms/Lennox-Gastaut genetics goes transatlantic | Beyond the Ion Channel

  2. Pingback: 2013 in review: top three lists and the gene finding of the year | Beyond the Ion Channel

  3. Pingback: Story of a genetic shape-shifter: SCN2A in benign seizures, autism and epileptic encephalopathy | Beyond the Ion Channel

  4. Pingback: Modifier genes in Dravet Syndrome: where to look and how to find them | Beyond the Ion Channel

  5. Pingback: Five questions you should be asking the ILAE Genetics Commission | Beyond the Ion Channel

  6. Pingback: TBC1D24, DOORS Syndrome, and the unexpected heterogeneity of recessive epilepsies | Beyond the Ion Channel

  7. Pingback: Papers of the week – next-level mutation classifiers and 3′UTR variants in Dravet Syndrome | Beyond the Ion Channel

  8. Pingback: Treatable causes of intellectual disability and epilepsy that you don’t want to miss | Beyond the Ion Channel

  9. Pingback: The return of the h-current: HCN1 mutations in atypical Dravet Syndrome | Beyond the Ion Channel

  10. Pingback: SLC25A22, migrating seizures and mitochrondial glutamate deficiency | Beyond the Ion Channel

  11. Pingback: The OMIM epileptic encephalopathy genes – a 2014 review | Beyond the Ion Channel

  12. Pingback: Living in a post-linkage world, craving knowledge | Beyond the Ion Channel

  13. Pingback: SCN1A – This is what you need to know in 2014 | Beyond the Ion Channel

  14. It is interesting to note that animal models of Dravet Syndrome exhibit similar variation in phenotype. Mice with the identical stop codon in Scn1a may range in phenotype from unaffected (often 50%) to SUDEP. These observations are made on genetically homogeneous strain backgrounds and even littermates with identical prenatal environment. This data indicates that stochastic developmental variation contributes to phenotypic variation. For example, the precise level of channel mRNA and protein expression in particular sets of neurons at critical developmental stages could vary among individuals and influence the final outcome.

    • Dear Miriam, this is actually an interesting observation that I wasn’t aware of. I was thinking that it might actually make sense to examine the large SCN1A-GEFS+ pedigrees again to see whether the phenotypes are distributed randomly – we had some initial ideas last year that it might be possible to develop a statistical test that would examine whether there is some familial component to phenotype severity. It might be worthwhile looking at this again. In terms of genetics, every attempt to chase up modifier genes will probably need a much larger number of families than we are currently aware of – and we might still not be able to distinguish stochastical effects from modifier genes.

Comments are closed.