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

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)

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

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

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

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

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

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

Rare variants and olive trees

Epic dimensions. 5,000 years ago, human civilization was getting off the ground in Mesopotamia. At some point, the early human pioneers decided to use pictures as letters and human writing was invented. Ox became aleph, which became alpha, which turned into literature, which finally turned into blogging. At around the same time that the Mesopotamian people invented the direct precursor of modern day tweets and text messages, rare genetic variants started spreading through the human population. In fact, all the rare variation that we see in humans today, had probably not been present prior to the chiseling of the first human words. Continue reading

Gephyrin, the inhibitory synapse and pathogenic microdeletions

GABA, postsynaptic. The molecular structure of the postsynapse has long been a mystery. Why do receptors cluster at a particular site and don’t simply float around all over the plasma membrane? The identification of postsynaptic scaffolding proteins answered some of these questions. However, it also became clear that inhibitory synapses are completely different from excitatory synapses. Now, a recent paper in Human Molecular Genetics finds that exonic deletions in gephyrin, the main structural protein of the inhibitory synapse, predispose to various neurodevelopmental disorders. Continue reading

AUTS2, regulatory elements and human evolution

Recurrent themes. The era of large-scale genomics in neurodevelopmental disorders has welcomed the discovery of several genes, which predispose to a wide range of neurodevelopmental disorders. While a connection to neuronal function is obvious for a few of them, the function of other genes remains cryptic. Now, a recent paper in PLOS Genetics investigates AUTS2, a gene that is both a candidate gene for autism and a gene that has changed dramatically in recent human evolution. Continue reading