Is it, or isn’t it? EFHC1 mutations in epilepsy

Back at the European Neurological Society I went to a session on “What every young neurologist should know”. And apart from a few general career comments, it was clear that the crucial skill a 21st century neurologist needs to learn, according to the organisers, was a thorough appreciation of genetics. 

And we can see why. Modern genetic investigations have completely revolutionised neurological subspecialties: More than 40 single-gene causes of movement disorders have been described, many of which are now tested for routinely in the clinical setting and can transform the diagnosis and management of affected patients. 

Epilepsy genetics research has been equally exciting, albeit with a variety of challenges. The topic seems to have been catapulted into the clinical consciousness with the emergence of the SCN1A story – mutations of this gene can both cause a severe epileptic encephalopathy (Dravet syndrome), but are also quite commonly found in all kinds of other (mainly childhood) epilepsy syndromes [1]. 

Even for this, most established single gene cause of epilepsy, the phenotypes are varied and somewhat unpredictable. The genetic basis of the more common childhood epilepsies are, like many common conditions with a genetic background, even more heterogeneous. And to everyone not directly involved with genetics, the picture gets murkier, because despite advances in technologies, the answers are not always straight-forward. As is the case with the EFHC1 gene and juvenile myoclonic epilepsy (JME). 

Ryan Subaran and colleagues [2] shed new light on a debate which, according to my old boss Deb Pal & Ingo Helbig [3] has been “one of the longest running sagas in epilepsy genetics”: Mutations in the EFHC1 gene have initially been identified through linkage studies as a possible cause for juvenile myoclonic epilepsy. These initial findings have since been replicated a number of times and an animal model was developed. 


Subaran et al. (2014)
Subaran et al. (2014) Epilepsia Early View

What Subaran et al. bring to the table now is a re-evaluation of the control samples used as comparison to assess likely pathogenicity of the found mutations. They show that the mutation-associated haplotype is not rare in healthy subjects with Hispanic (see the table above) and African American ancestry. It is tolerated in healthy individuals, casting doubt on the claims on its pathogenicity, more than ten years after its initial description. Helbig even goes so far to declare the gene retired on his blog.The story highlights a few issues with epilepsy genetics, but as Pal and Helbig put it:

“The interpretation of pathogenic rare variants according to a combination of statistical, population genetic and biologic foundations [is an issue] very much alive today in the exome era.” [3]

So whilst experimental genetic methods successfully make it into clinical use, technological advances alone will not solve give us a neat, causative variant on a silver plate. Given the relatively high frequency of variation in the healthy human genome, different lines of evidence are required to convincingly identify a mutation as causative for epilepsy. And where the focus appears to have pushed towards molecular characterisation of the mutation effects and animal models, Subaran et al. highlight nicely that population based genetics is an important prerequisite. 

[1] Mulley JC et al. (2005) SCN1A Mutations and Epilepsy. Hum Mut 25:535-42, DOI 10.1002/humu.20178
[2] Subaran RL et al. (2014) Pathogenic EFHC1 mutations are tolerated in healthy individuals dependent on reported ancestry. Epilepsia Early View, DOI: 10.1111/epi.12864
[3] Pal DK & Helbig I (2015) Commentary: Pathogenic EFHC1 mutations are tolerated in healthy individuals dependent on reported ancestry. Epilepsia Early View, DOI: 10.1111/epi.12906