Papers of the week – 15q11 duplications, Olig1 & Automated decision-making

Bild1

A productive week in epilepsy genetics.  Scientists and editors were certainly busy this week reporting novel variants and deletions as well the experimental and statistical advances for their interpretation.

A de novo GRIN2A missensmutation in early-onset epileptic encephalopathy. We and others have associated variants affecting the GRIN2A gene with a range of childhood focal epilepsy syndromes. Continue reading

Papers of the week – Encephalitis-antibodies, FAN1, Art and Parent-of-Origin Effects

Dennis' paper of the week

Biggest surprise this week: Imprinted genes interact with non-imprinted genes frequently. But first sequencing reports, statistical frameworks for rare variants analyzes and an impressive translational result.

A novel encephalitis with seizures and the analysis of the effects of antibodies. In their study published in LANCET NEUROLOGY Petit-Pedrol and coworkers characterized serum and CSF samples for antigens in 140 patients with encephalitis, seizures or status epilepticus as well as antibodies to unknown neurophil antigens. High titres of serum and CSF GABAA receptor antibodies are reported to be associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both, which could be exploited for immunotherapy with 15 patients.

Continue reading

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

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.

Continue reading

The genetics of treatment response in newly diagnosed epilepsy

Two questions. There are two main questions that we would like to answer with genetics in the field of epilepsy. First, are there genetic risk factors for epilepsies and if so, what are they? Secondly, are there genetic factors that help us understand how patients react to treatment, i.e. are there genes that predispose to response to antiepileptic drugs or that might be associated with side effects? While we have made much progress in answering the first question by identifying many epilepsy genes, there have been few answers for the second question, the field of pharmacogenomics. Now, a recent study in Human Molecular Genetics looks at potential genetic risk factors for the response to antiepileptic drugs in newly treated epilepsy. This is a study that needed to be performed and that we were waiting for. Continue reading

GRIN2A encephalopathy, epilepsy-aphasia and rolandic spikes

The GRIN2A triple. The idiopathic focal epilepsies are a group of childhood seizure disorders ranging from mild, self-limiting rolandic epilepsy to severe epileptic encephalopathies. The EEG feature of sharp-slow waves originating from the rolandic region is the unifying feature. As the rolandic region is part of the brain regions involved in speech production, acquired aphasia, i.e. loss of speech, can be a prominent feature in some patients. A strong genetic contribution in idiopathic focal epilepsies is assumed, but the genes involved have remained largely elusive. Now, three back-to-back publications in Nature Genetics highlight a prominent role of GRIN2A, probably the most counter-intuitive epilepsy gene ever found. 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

The return of TBC1D24

First of its kind. In 2010, a virtually unknown gene became the first epilepsy gene to be discovered through massive parallel sequencing techniques. This gene, TBC1D24, was found in two recessive families with different types of epilepsy. Afterwards, it became silent around this gene with no further findings. Now, a recent paper reports on a third family with a mutation in this gene with a complex phenotype of epileptic encephalopathy and movement disorders. As the mutation is located in an alternative exon of this gene, this raises important issues on how we identify and interpret mutations. Continue reading

A new spectrum unfolding – KCNT1 mutations in ADNFLE and MMPSI

A surprising finding. The genetic basis of many epileptic encephalopathies and familial epilepsies remains unknown. Novel sequencing technologies such as Next Generation Sequencing now offer the possibility to identify the genetic basis of these conditions. However, it is a rare event that a single gene is implicated in two completely different epilepsy subtypes. Such a finding has now been reported in Nature Genetics. The KCNT1 gene is found to be mutated in Malignant Migrating Partial Seizures of Infancy (MMPSI) and a severe form of Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). I doublechecked at least three times whether both papers actually talk about the same gene. Continue reading

The exome fallacy

Are you fully covered? My experience with a phenomenon I shall call exome fallacy began in 2011. While browsing the exomes of a few patients with epileptic encephalopathies, we wanted to have a quick look at whether we could exclude mutations in the epilepsy gene SCN1A in our patients through exome data. As some of you might already guess, the words “exome” and “exclude” don’t go well together and we learned the hard way that each individual exome covers certain parts of the gene quite well. However, if you expect your exome data to have sufficient quality to cover an entire gene in several individuals, you end up disappointed. But there is even more to the exome fallacy than you might think… Continue reading