EuroEPINOMICS-RES reloaded – reinventing a consortium

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Countdown. With the new trio exome data ready at the Sanger Institute, the data analysis within the RES consortium is immediate. However, much has happened in the last 12 months that will impact on how we analyze the data and what this data means. The RES consortium will have their large teleconference today, June 19th to discuss these issues and there is one central issue that we need to face – the issue of data sharing. Let me put together a brief post on my personal view of this (not necessary reflecting the official views of the consortium). In addition, there is another, even more important issue to be solved. Who are we? Continue reading →

ST3GAL3 and exome sequencing in autosomal recessive West Syndrome

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Autosomal recessive West Syndrome. Exome sequencing and other high-throughput sequencing technologies work best in the identification of recessive disorders. While many cases of West Syndrome are thought to be the result of de novo mutations, recessive inheritance is seen in a subset of patients. In a recent paper in Epilepsia, Edvardson and colleagues now report mutations in ST3GAL3 in a consanguineous Palestinian family with four affected individuals with West Syndrome. This report takes us deep into the chromosomal anatomy of the linkage region, raising the question at what point we can claim that a gene is found. Continue reading →

Genes, patents and the Myriad story

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When genes meet the law. Last week, the Supreme Court of the United States of America (SCOTUS) ruled that genes are not patentable, a decision that will be known as the “Myriad Decision”, named after Myriad Genetics, a commercial laboratory that is the single provider for BRCA1/2 testing in breast cancer and ovarian cancer in the United States. For more than a decade, Myriad has had virtually exclusive rights to the genetic analysis of both genes, given a large number of patents surrounding BRCA1/2 analysis. Continue reading →

The wonders of Medical Neuroscience

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MOOC. People have been hailing Massive Open Online Courses (MOOCs) as the next big thing in higher education. Accordingly, the number of people complaining about their failures is now substantial. MOOCs are following the usual hype cycle and we could close the post here. Then again, I recently became a MOOC disciple and need to vent some  praise of a course on the Coursera platform that people reading this blog should be aware of: Medical Neuroscience presented by Leonard White (Duke).

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DEPDC5, meet the mTOR pathway – a novel mechanism in genetic focal epilepsies

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Variable foci. A few weeks ago, we discussed the recent gene finding in Familial Partial Epilepsy with Variable Foci, a rare but puzzling familial epilepsy syndrome. DEPDC5 was identified as the culprit gene. However, the potential function of the gene product left researcher scratching their heads. Now, a recent paper in Science suggests that DEPDC5 might interact with the mTOR pathway, the master regulator of growth. Should we reconsider the role of the mTOR pathway in genetic focal epilepsies? Continue reading →

The eye of the tiger, brain iron and the beta-propeller

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NBIA. Neurodegeneration with brain iron accumulation (NBIA) is a group of mainly recessive disorders that present with progressive dystonia and dementia. The common feature of these diseases is the excessive accumulation of iron in the basal ganglia. NBIA is very rare and usually not discussed in the context of epilepsy. However, a recent paper in Brain reviews the phenotypes of beta-propeller associated neurodegeneration (BPAN), a novel X-linked disorder with brain iron accumulation. In childhood, the phenotype shares similarities with atypical Rett syndrome and other epileptic encephalopathies, raising the question to what extent the epilepsies that we investigate may be neurodegenerative disorders. Continue reading →

Less is more – gene identification in epileptic encephalopathies through targeted resequencing

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Exome no more. Over the last 15 months, we have repeatedly discussed how exome sequencing or genome sequencing is applied to neurodevelopmental disorders in order to discover new candidate genes and to assess the role of known candidate genes. We have also wondered sometimes whether exome sequencing is the most straightforward approach. Now – outpacing the two large international consortia using exome sequencing in epileptic encephalopathies – a recent study in Nature Genetics uses a different approach to uncover the genetic basis in 10% of patients with epileptic encephalopathies.  Targeted resequencing or gene panel analysis is a hybrid technology between candidate gene sequencing and next generation sequencing and focuses only on a subset of candidate genes. While their study provides a comprehensive overview over the genetics of rare epilepsy syndromes, it raises the question whether the era of large-scale exome sequencing is coming to a natural end. Continue reading →

Exome sequencing in epileptic encephalopathies – a classification of de novo mutations

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Trio-sequencing your clinic. From the perspective of a child neurology clinic, I often wonder how much information we would gain if we performed trio exome sequencing for de novo mutations systematically in all our patients with difficult-to-treat epilepsies. Many of these patients have epilepsies that are difficult to classify and they have not been included in our existing EuroEPINOMICS working groups on defined syndromes. Now, a recent publication in Epilepsia gives us an idea what we will find if we perform family-based exome sequencing in patients with unclassified epileptic encephalopathies. Basically, you will find SCN1A and CDKL5 plus mutations in several genes that are likely pathogenic. But there is much more to this issue, which motivated me to come up with a classification scheme for epilepsy-related de novo events.  Continue reading →

Live at Covent Garden – the ERC Starting Grant Interviews

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On stage. I just got back from Brussels where I had to defend my ERC Starting Grant in front of the Neuroscience Panel. The European Research Counsil (ERC) Starting Grants are prestigious excellence grants and I was lucky enough to be invited for the famous second round. This second round requires the applicants to go to Brussels in order to give a 10-15 min presentation and defend the application on the 24th floor of the Covent Garden building. It provides a wonderful view of the city, but nobody really bothered taking this in. Let’s use the opportunity to quickly discuss grants, funding and the future of epilepsy genetics. Continue reading →

Sturge-Weber syndrome explained – somatic mutations in GNAQ

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Phakomatoses. There are a group of disorders that affect both the skin and the central nervous system. These disorders, called neurocutaneous disorders or phakomatoses, may result in epilepsy or intellectual disability, depending on the extent to which the brain is affected. While a genetic basis for some neurocutaneous disorders including Tuberous Sclerosis Complex (TSC) and neurofibromatosis is known, the etiology of other neurocutaneous diseases remains unknown. Now, a recent paper in the New England Journal of Medicine reports on the genetic alterations underlying one of the most common neurocutaneous disorders, Sturge-Weber syndrome. Continue reading →