The 16p11.2 microdeletion: assessing the phenotypic range

The 16p11.2 story. Among the various microdeletion and microduplication syndromes located on human chromosome 16, the 16p11.2 microdeletion has unique position. Historically, this microdeletion was the first of the “neurodels” to be identified through association studies in autism, where it can be identified in 0.5% of patients. However, there is more to the phenotypes of the 16p11.2 microdeletion, which is now addressed in a recent paper assessing the full phenotypes in 72 microdeletion carriers. 16p11.2 therefore represents one of the best-investigated microdeletions to date. Continue reading

Validation of rare variants – the power of finding anything at all

How much? Last week, we discussed the probability of finding de novo variants in patients with epileptic encephalopathies, but our calculations were only half the story. Genes that are identified through genome-wide sequencing technologies are often validated in additional cohorts. In many cases, we will only be able to establish a given gene as causative if we find another patient with a mutation in this gene. I was therefore asked to write an additional post on power calculations for rare variants in validation cohorts. Let me tell you the story how I stumbled across a little bit of almost forgotten high school math. Continue reading

The Hippocampus Conspiracy

Slightly misleading. The green and blue histological staining that has become the EuroEPINOMICS logo features a human hippocampus, a part of the human brain that is particularly important in human epilepsy. Temporal Lobe Epilepsy (TLE) is the most common epilepsy in adults and involves the hippocampal region. Ironically, TLE is the human epilepsy that has always been at odds with genetic research. Let’s review what we know about the genetics of TLE and “hippocampal genetics”. Continue reading

A new twist on an old gene: EFHC1 in epileptic encephalopathy

A peculiar gene. There is one gene in the small world of epilepsy genetics that has always troubled me. A gene that has an unknown function and is not expressed in the postnatal brain, but is well established as one of the few genes for autosomal dominant Juvenile Myoclonic Epilepsy (JME). This gene is EFHC1. Now, a recent paper in Epilepsia reports EFHC1 as a possible candidate gene in autosomal recessive epileptic encephalopathy with neonatal onset. The mystery surrounding this gene continues. Continue reading

SpotOn 2012 is on air

The biggest European meeting on Science online – policy, outreach, tools – started this Sunday. SpotOn brings  open source coders, librarians, scientists from a variety of fields, and publishers together in London.

You can follow the keynotes and sessions online and evaluation and comments can be followed in real time on Twitter. #solo12 is hashtag of the overall conference, the individual sessions have their own tags. Continue reading

What’s in a phenotype? – the EuroEPINOMICS BENCH database

The backbone. As we have started a new round for BENCH introductory sessions with new collaborators, I thought that it might be timely to talk a little bit about our BENCH phenotype database and the concepts behind it. In addition to the purely technical aspects, there is a more fundamental question behind this: how do we want to document and store epilepsy phenotypes for research purposes, how do we find the balance between precision and efficiency? Continue reading

CACNA1A variants as genetic modifiers in Dravet Syndrome

Genetic modifiers. Dravet Syndrome, formerly Severe Myoclonic Epilepsy of Infancy (SMEI) is a severe epileptic encephalopathy starting in the first year of life. More than 80% of cases of Dravet Syndrome are caused by loss-of-functions mutations in SCN1A, a voltage-gated sodium channel predominantly expressed on GABAergic interneurons. Now, a recent paper in Neurobiological Disorders investigates the role of CACNA1A variants as possible genetic modifiers in Dravet Syndrome. Continue reading

Exome sequencing in epileptic encephalopathies – the powers that be

The power, over and over again. I must admit that I am thoroughly confused by power calculations for rare genetic variants, particularly for de novo variants that are identified through trio exome sequencing. Carolien has recently written a post about the results we can expect from exome sequencing studies. For a current grant proposal, I have now tried to estimate the rate of de novos using a small simulation experiment. And I have realized that we need to re-think the concept of power. Continue reading

Jumping genes in the brain – single neuron sequencing of L1 retrotransposons

The not so static genome. We usually think that our genome is static and that differences between cell types usually arise through mechanisms that do not necessarily involve alterations of the DNA structure. This suggestion has been challenged by initial data suggesting that retrotransposons may be particulary active in neurones. Now, a recent study in Cell investigates the role of jumping genes using single-cell sequencing of neurons.

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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