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

Pushing the boundary – 27 novel epilepsy genes in the 2017 DDD study

DDD. On January 25, the most recent publication of the Deciphering Developmental Disorders (DDD) study appeared online in Nature. This unprecedented study analyzed the data of 4,293 patient-parent trios with existing data from 3,287 published trios to identify de novo mutations in neurodevelopmental disorders. A study of this size has many aspects that are difficult to fully cover within the limited space of a journal article. Browsing through the data is interesting and will be the foundation for many studies utilizing this data in the near future. Within this first comprehensive blog post of 2017, I try to answer the question what this study means for the field of epilepsy genetics. For example, it provides us with more than 20 epilepsy genes that we did not know about so far. 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

The Cavatica experience – running epilepsy exomes in the cloud

End of the year. The final weeks of the year are always a time when my curiosity for bioinformatics takes over. Four years ago, I was trying to teach myself sufficient command line and bioinformatics to run Denovogear on my computer. Now the field has moved on, from command line language to solutions that aim at bringing data closer to researchers. I hijacked a platform that was initially built for cancer research, CHOP’s Cavatica platform that was developed with Seven Bridges Genomics. In the same way as a few years ago, I started out with a simple question: Can I take an exome completely apart and then re-analyze it to find the SCN1A mutation in DRA1? Continue reading

FOXG1 – an epilepsy gene involved in brain development

Forkhead. In our Epilepsiome series we are reviewing all major epilepsy genes. This week, we discuss FOXG1, a gene previously described as the cause for a congenital variant of Rett Syndrome. However, since its initial discovery in 2008, a much broader spectrum has been recognized. FOXG1 syndrome typically includes developmental delay and microcephaly. Many patients have severe, early-onset epilepsy and a prominent hyperkinetic movement disorder. In addition, some patients have brain malformations. Here is a brief introduction to our Epilepsiome review of FOXG1, an epilepsy gene that stands out from other causes of genetic epilepsies given its prominent role in forebrain development.

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MECP2 – Rett Syndrome in the era of exome-first studies

Rett. We have written very little about MECP2 on Beyond the Ion Channel. MECP2 is the gene for Rett Syndrome, a neurodegenerative disorder almost exclusively affecting females. Classical Rett Syndrome is characterized by developmental regression in the first two years of life and the development of distinctive hand movements, which historically led to Rett Syndrome being considered a recognizable entity. This blog post is the introduction to our MECP2 Epilepsiome page. However, in 2016, a time when many genes are re-defined by exome studies, I was wondering whether Rett Syndrome is still the classical syndrome that I initially learned about.

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ALG13 – rethinking the glycosylation code

The sugar code. Many proteins in the human body undergo post-translational modification. A common mechanism to modify the function of proteins is a process called glycosylation, the adding of carbohydrate residues to protein. Glycosylation is probably the most complex post-translational modification, critically important to various physiological functions and therefore tightly regulated in cells. Accordingly, genetic disorders that interfere with glycosylation may present as severe, multisystem disorders. However, it is increasingly recognized that many congenital disorders of glycosylation have an exclusively neurological phenotype. Here is an update on ALG13 epileptic encephalopathy, a recently identified disease entity that may account for up to 2% of Infantile Spasms in females. Continue reading

A clinician’s guide to genetic test selection: navigating the Wild West

The Wild West. The diagnostic genetic testing landscape in 2016 is a paradox. In theory genetic testing has never been more widely available clinically, with over 20 diagnostic laboratories in the US alone offering a variety of genetic testing options for patients with epilepsy, ranging from single gene testing to NGS panels to whole exome sequencing. However, access to and reimbursement of genetic services varies widely, with no consensus on an approach to testing or professional guidelines to aide clinicians. Here is our brief guide to epilepsy genetic test selection for busy clinicians. Continue reading