Ultra-rare genetic variants in familial epilepsies

The final frontier. The last five years have seen enormous progress in understanding the genetic basis of sporadic severe, treatment-resistant epilepsies due to de novo mutations. However, there has been much less progress in understanding the basis of familial epilepsy, which has historically been the major focus of epilepsy genetics. Particularly small families with mild epilepsies are challenging to solve, with the exception of rare families with pathogenic variants in known epilepsy genes. Exome-first approaches in familial epilepsy are particularly challenging given the sheer amount of variants segregating in small families by chance. In a recent publication by the Epi4K Consortium, a novel approach is presented to identify the genetic basis of familial epilepsies, overcoming the limited power of small families by analyzing rare variants in probands in a case/control study design. Here are some fascinating insights from this study. Continue reading

The Focal Epilepsy Conference 2017 – an invitation to the Faroe Islands

Retreat. Part of the Kingdom of Denmark, the Faroe Islands are an archipelago between the Norwegian Sea and the North Atlantic halfway between Norway and Iceland. From May 24 to 26, 2017, the international epilepsy community will retreat to the Faroe Islands for a conference on the mechanisms of focal epilepsies. With this post, I am inviting clinicians and scientists who typically read our blog to this meeting. Take a quick glance at the program and you will understand why I think that this meeting is interesting. In 2017, a conference on the mechanisms of focal epilepsy has become a conference with a main focus on genetic mechanisms. Here is how our perception of the genetics of focal epilepsies changed over the last 18 years and why a trip to the middle of the North Atlantic may be worthwhile for you. Continue reading

ARX – a 2017 Update

Aristaless. When you look at the genes for neurodevelopmental disorders identified in modern-day exome studies, one gene is notably absent: ARX. The X-chromosomal aristaless related homeobox gene was one of the first genes for epilepsies and brain malformations to be discovered. Pathogenic variants in ARX can be identified in male patients with a variety of neurodevelopmental disorders including idiopathic West Syndrome – accordingly, ARX is on the differential list for patients with intractable infantile spasms without a known cause. One of the reasons why we hear so little about ARX is the fact that this gene is poorly covered in exomes. Furthermore, one of the major disease-causing variants is a repeat expansion that cannot be assessed through exome studies at all. Here is a brief summary of what we know about ARX in 2017. Continue reading

Scientific mistakes and the Book of Kells

Dublin. In September 2016, my way back from the ECE in Prague led through Dublin where I was able to spend two days, following an invitation by the Science Foundation Ireland. Given that there was a gap between the Prague congress and the day that I was supposed to be on-site, I arrived in Ireland early and spent 24h in Dublin. When I took a stroll into the city, I ended up in Trinity College and the exhibition about the Book of Kells, a 1200 year-old manuscript containing the Four Gospels of the New Testament. One part of the exhibition raised my interest, as it discussed the way that eighth century Irish scribes dealt with mistakes – I thought that this historical view would be an interesting introduction to review how we deal with scientific mistakes today. Continue reading

GABRB3 – from febrile seizures to epileptic encephalopathies

Beta-3. Even though the gene for the beta-3 subunit of the GABA-A receptor (GABRB3) has not been mentioned frequently in the context of epilepsy genes, it is a gene that is frequently involved in genetic changed that give rise to epilepsy. Given that GABRB3 is one of the genes found within copy number changes on chromosome 15, it may predispose to human epilepsies through various genetic mechanisms including copy number variations and de novo mutations. In a recent publication in Neurology, we reviewed the phenotypes of patients with GABRB3 variants and found an unusual complexity of sporadic and familial cases. Here are three things that I have learned about GABRB3. Continue reading

Year 1 of the Epi25 Collaborative – the first 6,000 epilepsy exomes

At this time one year ago, the Epi25 Collaborative, a project of unprecedented scale, got the green light to start sending DNA to the Broad Institute for sequencing. More than 200 epilepsy researchers from nearly every epilepsy genetics project in the world sent 9,000 DNA samples to the Broad Institute for exome sequencing. Epi25 hopes to illuminate the complex nature of common epilepsies, ultra-rare variants, and bring more of the de novo mutations in encephalopathies into the “causative” group. Never before has such a massive collection of epilepsy samples been assembled so swiftly, truly from around the globe, with such grand aspirations. Continue reading