Genetic imaging in Dravet Syndrome – variation on a theme?

Networks in the brain. While I am waiting to hear back about my ERC starting grant application on genetic imaging, I wanted to use the waiting time to introduce a small pioneer study that we performed on functional imaging in Dravet Syndrome. Dravet Syndrome, one of the most prominent genetic epileptic encephalopathies, is due to mutations in SCN1A. The EEG findings progress from an initially unremarkable EEG to frequent generalized activity. Functional MRI offers a possibility to investigate the network underlying these discharges and to pinpoint brain regions involved in generating the epileptiform activity. Given that patients have a common genetic finding, the assumption that discharges are generated by identical networks is intriguing. However, we found that things might not be as simple as that. Continue reading

Transmission of rare variants in parent-offspring trios – power or no power?

My untested assumption. Recently, I have boasted quite a bit about the power of the trio design, i.e. the inclusion of patients and parents in the analysis of rare genetic variants. Rare variants, in contrast to monogenic variants that arise de novo, are usually transmitted from unaffected parents and are the big unknown of modern day genetic studies. Much of the missing heritability may be accounted for by rare variants, but identifying these variants from genomic noise is difficult. Power calculations for association studies usually suggest that thousands, if not tens of thousands, of patients are necessary to identify these variants with sufficient statistical certainty, a sample size that the field of epilepsy research may never arrive at. So what about switching to parent-offspring trios? Would this help us? Follow me on a brief statistical journey through the land of rare variants. Continue reading

ST3GAL3 and exome sequencing in autosomal recessive West Syndrome

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

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

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

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

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

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