Tag Archives: autism

Papers of the week – WES Meta analysis, Dravet mice & large sequencing studies

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Bild1Time flies – already thursday night again.  Here are updates on study designs to identify rare pathogenic mutations in neurodevelopment diseases, an epilepsy animal model study as well as novel statistical frameworks for large genetic screens.

The placebo effect. In a recent paper in Science Translational Medicine the group of Kam-Hansen investigated the effect of altered placebo and drug labeling changes and its outcome in patients with episodic migraine. Their results suggest that the placebo accounted for more than 50% of the drug effect.

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A PhD in genomics – lessons learned

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This is it! With finishing my PhD I have become an “adult” member of the scientific Graduierungcommunity. I grew out of a bachelor in biochemistry on transfection methods in neuronal cell lines, a research semester in Canberra with focus on B-cell immunology and master into a  PhD in epilepsy genomics. I was involved in the EPICURE IGE copy number projects and recently my work changed to the analysis of rare variants in RE and IGE in the EUROepinomics framework. During this time I was involved in the identification of variants in RBFOX genes and GRIN2A as well as other risk factors which are currently in review. I share my experience and thoughts and hope they help others who are about to or have just started their thesis. The aspects reflect my personal view and some are specific for graduation in disease genomics. Continue reading →

Papers of the week – Comorbidity clusters, Epigenomic annotation & exome-based TDT

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Finally, I have finished my PhD. Bild1After focussing on writing and defending my thesis for the last few months, I am now ready to focus on research again. Because I am understandably in a very happy mood, this week’s selection of papers also reflects the fun aspects of science beside neurogenetics and genomics. Continue reading →

Story of a genetic shape-shifter: SCN2A in benign seizures, autism and epileptic encephalopathy

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The other sodium channel gene. The week before Christmas, the Kiel group identified its first patient with SCN2A encephalopathy. At the same time, a questionably benign SNP in the same gene is haunting our Israel Epilepsy Family Project. Time to review the mysterious SCN2A gene that initially entered the scene as a candidate for a rare, benign familial epilepsy syndrome – only to return as one of the most prominent genes for autism, intellectual disability, and epileptic encephalopathies to date. Continue reading →

Papers of the week (w47)

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Dennis' paper of the weekThursday again already? Well, after the positive feedback from colleagues and friends I must continue. I like ambitious goals and hope that the epilepsy genetics community finds this new series on papers of the week helpful. Let’s start with a Science paper by McConnell and collaborators on somatic copy number variations in neurons, a paper that was also mentioned in a recent post. I wanted to know more about the single cell sequencing methodology. Continue reading →

Beneath the surface – the role of small inherited CNVs in autism

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Grey zone. Structural genomic variants or copy number variations (CNV) can be reliably assessed using array comparative genomic hybridization (array CGH) or Single Nucleotide Polymorphism (SNP) arrays.  However, for deletions or duplications smaller than 50-100 kB, these technologies have a poor detection rate with many false positive and false negative findings unless platforms are used that target specific candidate regions. Exome analysis, on the other hand, is capable of assessing genetic variation reliably on the single base-pair level. Between both technologies, there is a grey zone of structural genomic variants that are difficult to detect; CNVs smaller than 50 kB are often difficult to assess, and the extent and pathogenic role of these small CNVs is unclear. Now, a recent paper in the American Journal of Human Genetics manages to detect small CNVs through exome data. Their analysis in patients with autism, parents, and unaffected siblings suggests a contribution of small inherited CNVs to the overall autism risk. Continue reading →

Dravet Syndrome and rare variants in SCN9A

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How monogenic is monogenic? Dravet Syndrome is a severe epileptic encephalopathy starting in the first year of life. More than 80% of patients have mutations or deletions in SCN1A, which makes Dravet Syndrome a relatively homogeneous genetic epilepsy. In addition to SCN1A, other genetic risk factors for Dravet Syndrome have been suggested, and current, large-scale studies including EuroEPINOMICS-RES are studying the genetic basis of the minority of Dravet patients negative for SCN1A. A recent paper in Epilepsia now suggests that a significant fraction of patients with Dravet Syndrome also carry rare variants in SCN9A in addition to the mutations in SCN1A. Is a mutation in SCN1A not sufficient to result in Dravet Syndrome, but needs additional genetic modifiers? Continue reading →

Cold fusion – joining exome datasets to identify autism genes

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Mergers and acquisitions. Invariably, genetic research in neurodevelopmental disorders is moving towards joint analyses of large datasets. While the methodology of meta-analysis is well established for genome-wide association studies, the joint analysis of exome datasets comes with many question marks. Now, a recent paper in PLOS Genetics pioneers the field of joint exome data analysis for association studies in autism. This paper highlights some unexpected facets of rare variant analysis. Continue reading →

The genetics of emergent phenotypes

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This article was written Kevin Mitchell and first published on his blog “Wiring The Brain” and appears here with his consent.

Why are some brain disorders so common? Schizophrenia, autism and epilepsy each affect about 1% of the world’s population, over their lifetimes. Why are the specific phenotypes associated with those conditions so frequent? More generally, why do particular phenotypes exist at all? What constrains or determines the types of phenotypes we observe, out of all the variations we could conceive of? Why does a system like the brain fail in particular ways when the genetic program is messed with? Here, I consider how the difference between “concrete” and “emergent” properties of the brain may provide an explanation, or at least a useful conceptual framework. Continue reading →

“Meta-channelopathies” – RBFOX1 deletions and human epilepsy

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Man is built to seize. When Hughlings Jackson made this famous comment pertaining to the inherent hyperexcitability of the human brain in response to a wide range of different stimuli, he probably didn’t anticipate the mechanisms of splicing regulation. Our CNS is actively protected from hyperexcitability through directed splicing of ion channel mRNA. Now, a recent study in Epilepsia finds that these mechanisms may be dysfunctional in human epilepsy. Continue reading →