Publications of the week – CNTNAP2, DEPDC5, and autism whole-genome sequencing

Issue 4/2015. Trying to keep up with the publications of the week in the field, we have selected three manuscripts this week, which challenge some of our well-established beliefs. It’s about an autism gene losing its statistical support, a familial epilepsy gene rediscovered in focal cortical dysplasia, and the surprises of whole-genome sequencing in familial autism. Continue reading

Infantile Spasms/Lennox-Gastaut genetics goes transatlantic

Joining forces. The EuroEPINOMICS-RES consortium and Epi4K/EPGP are currently joining forces for genetic studies on epileptic encephalopathies. A first collaborative study focuses on de novo mutations in Infantile Spasms and Lennox-Gastaut-Syndrome. In the last two years, after decades of disappointment, we have finally managed to accomplish a breakthrough in understanding the genetic basis of epileptic encephalopathies. The method of trio-based exome sequencing works amazingly well to identify the genetic cause, and the field currently has the crucial momentum to reach the next level of research. Let’s briefly review why we need international collaborations to disentangle the genetic architecture of the epileptic encephalopathies. Continue reading

Pharmacogenomics for epilepsy

The treatment options for epilepsy must undoubtedly be improved. More than 20 antiepileptic drugs are licensed but in 30% of patients seizures are not controlled, despite treatment with a number of anti epileptic drugs and the response to medication is difficult to predict. Antiepileptic medications can cause severe adverse reactions and increase the risk of fetal malformations in women taking them during pregnancy. The differences in drug response and the occurrence of rare adverse reactions are believed to be caused by variants in the genetic makeup of individuals. Knowledge of these variants would help us to predict drug response and adverse drug reactions. This personalized treatment would help us to select medications for each individual.

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The mosaic brain – single neuron copy number variations in humans

Variability. It has been rumored for quite some time, but only now is solid evidence present to show this phenomenon: the high degree of genomic diversity of human neurons. In a recent paper in Science, the genomic diversity among frontal brain neurons is explored on a cell-by-cell basis. The results are breathtaking: up to 40% of frontal cortex neurons have altered genomic material affected by large deletions or duplications. This study provides the linchpin for a plethora of new investigations aiming to understand the impact of this phenomenon in health and disease. Continue reading

Sturge-Weber syndrome explained – somatic mutations in GNAQ

Phakomatoses. There are a group of disorders that affect both the skin and the central nervous system. These disorders, called neurocutaneous disorders or phakomatoses, may result in epilepsy or intellectual disability, depending on the extent to which the brain is affected. While a genetic basis for some neurocutaneous disorders including Tuberous Sclerosis Complex (TSC) and neurofibromatosis is known, the etiology of other neurocutaneous diseases remains unknown. Now, a recent paper in the New England Journal of Medicine reports on the genetic alterations underlying one of the most common neurocutaneous disorders, Sturge-Weber syndrome. Continue reading

Hypermutability of autism genes: lessons from genome sequencing

Pushing past the exome. Family exome sequencing has become a standard technology to identify de novo mutations in neurodevelopmental disorders including autism, schizophrenia, intellectual disability and epilepsy. Despite the many advances in the field, exome data is confusing and difficult to interpret. Accordingly, we were wondering what the increase from exome sequencing to genome sequencing might add other than more data and more questions. Now, a recent paper in Cell reports on family-based whole-genome sequencing in autism. And some of the results are quite surprising. 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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EuroEPINOMICS family studies go whole genome

The EuroEPINOMICS live ticker. During the last ten months, the focus of the EuroEPINOMICS consortium on Rare Epilepsy Syndromes (RES) has been the trio analysis in patients with epileptic encephalopathies. The RES subproject also aims at analysing the genetics of rare familial epilepsies. There have been ongoing discussions about the best way to get the analysis started. Last week, we finally “sealed the deal” for whole genome analysis in RES families. The EuroEPINOMICS RES consortium will collaborate with the CoGIE partner Luxembourg Centre for Systems Biomedicine (LCSB), the Institute of Systems Biology, Seattle USA (ISB) and Complete Genomics to analyse whole genome data of families with Rare Epilepsy Syndromes with an expected capacity of 100 genomes. But why exactly are we thinking about trading exomes for whole genomes? Continue reading

The years of our fathers: paternal age and the rate of de novo mutations

Aging fathers. An increase in risk of aneuploidies, i.e. chromosomal aberrations such as Trisomy 21, is well established with maternal age.  Whether the paternal age also increases the risk for disorders in the offspring had long been disputed. However, a connection between paternal age and autism has been found in recent years. Now a recent study in Nature finds a surprisingly strong correlation on the genetic level… Continue reading