KCNA2 – an epilepsy gene in hereditary spastic paraplegia

HSP. I have to admit that the hereditary spastic paraplegias are not mentioned all that frequently on our blog.  The main reason is that there is little overlap between early-onset epilepsies and adult-onset progressive neurodegenerative conditions that are characterized by spasticity and weakness in the lower extremities. In a recent publication, we described an epilepsy gene that became an HSP gene, showing an unusual overlap between both groups of conditions and establishing a novel mechanism in HSP pathogenesis. Here is a continuation of the KCNA2 story. Continue reading

The first Online Symposium: Rare Genetic Variants Associated with Neurodevelopmental Disorders

Online. Last week, we held the first online symposium on “Rare Genetic Variants Associated with Neurodevelopmental Disorders”. The meeting covered seven topics which included different genomic approaches used to unravel the genetic architecture of neurodevelopmental disorders and cognitive traits. In total, 117 participants joined the meeting with a peak of 72 participants listening to a presenter. Continue reading

Shortening the diagnostic odyssey – exome sequencing for white matter abnormalities

Background on whole exome technology. To explain the various ways of obtaining genetic information, I often refer to an encyclopedia set as a representation of our genome. All of the information which makes us who we are is written in a 4 letter code (A, T, G, C) in our genome or ‘encyclopedia set’ and is contained within our chromosomes or ‘volumes’. We have two sets of each volume, one from mom and one from dad. Targeted panels read a select number of genes or ‘chapters’ regarding only those which are known to be associated with white matter changes. Whole exome sequencing (WES) reads all of the coding sections, approximately 20,000 genes in total, but none of the extra information. This noncoding information would represent the appendices, figure legends, and foot notes. Whole genome sequencing (WGS) reads everything cover to cover. Continue reading

SYNJ1 links Parkinson’s disease to epileptic encephalopathy

Duality. Earlier this week, our Luxembourg collaborators came to visit us at CHOP to discuss our current and future projects. We discussed potential overlaps between the diseases that both our groups are mainly involved in, namely Parkinson’s disease and genetic epilepsies. In fact, we had just published on one of the overlapping genes recently, a gene that we accidentally stumbled upon through our genome sequencing projects. Here is the story of SYNJ1, a gene involved in neurodegenerative phenotypes that link early-onset Parkinson’s disease and epileptic encephalopathy. Continue reading

The two faces of GABRA1 – from familial epilepsy to epileptic encephalopathy

Inhibition. GABA is the main inhibitory neurotransmitter in the the Central Nervous System. Given that epilepsy is typically associated with increased excitability, all mechanisms related to GABA signaling are of natural interest to the epilepsy community. Almost 15 years ago, mutations in GABRA1, coding for alpha-1 subunit of the GABA-A receptor, have been identified in familial Juvenile Myoclonic Epilepsy, but there has been relative silence around this gene since. Now, two publications highlight the other side of GABRA1 as a gene for epileptic encephalopathies, putting the GABA receptor into the spotlight again.

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Nothing’s for sure, that’s for sure: Evaluating variants of uncertain significance

VUS. In recent EpiGC posts, we discussed how laboratories evaluate sequence variants and the challenges of communicating variants of uncertain significance (VUS) to patients. While VUS results can be frustrating, by working together clinicians and laboratories may accumulate additional evidence that enables a more definitive variant classification. But how, you ask? Well, there are several ways . . .

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The GRIN spirit – entering a new era of collaborative pediatric genomics

Completed. Last week, we completed the recruitment for one of the more visionary projects at CHOP that we are involved in – the epilepsy pilot project of the Genomics Research and Innovation Network (GRIN), a collaboration between CHOP, Boston Children’s Hospital, and Cincinnati Children’s Hospital. Here is my personal take on GRIN and why I think that forming, building, and expanding GRIN is so important in our current research environment. Continue reading

Five things I learned about SCN2A in Chicago

SCN2A. Last Thursday, I hopped on a plane to Chicago to join the first FamilieSCN2a Foundation Conference. SCN2A, one of the most common genes in genetic epilepsies, has emerged as a gene with a broad range of phenotypes, which makes understanding this gene relatively complicated. I am very happy that the SCN2A community is currently coming together to provide a platform for patient initiatives and connections to clinicians and researchers. Here is my list of five things I learned about the genetic shape-shifter in Chicago. Continue reading

Zeroing in on FAME – the dilemma of familial epilepsies

FAME. Some familial epilepsy syndromes are notoriously resistant to gene discovery. Familial Adult Myoclonus Epilepsy (FAME), a rare but distinct familial epilepsy, has been one of the familial epilepsy syndromes that has been around for more than a decade. Despite the power of modern massive parallel sequencing technologies, this syndrome has been hard to tackle.  In a recent publication, we take a small step in narrowing down the region for the FAME gene. Let’s use this opportunity for a reality check of the somewhat disappointing state of gene discovery in familial epilepsies in 2016 and what we can do about this. Continue reading

Misusing the concept of epileptic encephalopathy – on purpose

EEs. The concept of epileptic encephalopathy refers to a process where epileptic activity impairs overall brain function, including cognitive function, language, and behavior. In a recent commentary in Epilepsia, our current use and misuse of the concept of epileptic encephalopathy is reviewed critically. In summary, the authors criticize that epileptic encephalopathy is used as a diagnostic category rather than a description of the actual epileptic process, suggesting that another term may be necessary for the group of patients with intellectual disability and epilepsy where we often find a genetic etiology. In this blog post, I would like to plead guilty on behalf of the epilepsy genetics community for having misused the concept of epileptic encephalopathies for almost a decade. And we have done this for at least three different reasons. Continue reading