The RES-experiments: what results can be expected

Now the experiments to find de novo variants for epileptic encephalopathies within the Euroepinomics RES-project are well underway and first data are coming out, it is a good moment to pause and think about what results we can expect, and how these should be interpreted. For this it is very nice that recent large experiments in autism have provided so much useful data. In this post, I will explore what we can expect in experiments in which we perform whole exome sequencing in a group of patients and their parents to identify de novo variants that could be the cause of the disorder.

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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

21st century digital boy: The Kiel Young Investigators’ Meeting

The children of the genomic revolution. There aren’t many possibilities for young researchers in epilepsy research to get together independently. Accordingly, we were in the fortunate position to host the first meeting for young researchers in pediatric epileptology in Kiel last week. I was asked by some participants to write a post on this. There were, however, two very specific instructions. First, I was asked to write about “Generations X and Y” and the resulting conflicts in science. Secondly, I was told not to write an ordinary meeting report, but something different… 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

Of angels and interneurons

Angelman Syndrome and UBE3A. Angelman Syndrome is a severe neurodevelopmental disorder characterized by intellectual disability, typical facial features and a usually happy demeanor. Patients with Angelman Syndrome usually do not acquire active speech and often show a characteristic, atactic gait. Also, patients with Angelman Syndrome have a characteristic EEG pattern and many children have seizures. Angelman Syndrome is a genetic disorder due to loss of function of UBE3A, a ubiquitin ligase expressed in the CNS. Ubiquitin ligases are the bin collectors of the cell. By attaching ubiquitin to proteins, proteins are labelled for cellular degradation. How a malfunction of a cellular garbage truck causes such a complex neurodevelopmental disorder is poorly understood. A recent study, however, points out an important role for interneurons…. Continue reading

Mutations don’t always cause disease, quite the opposite

A mutation in APP protecting against Alzheimer’s disease. Alzheimer’s disease is one of the leading causes of dementia in the Western world. In rare familial forms of Alzheimer’s disease, variants in the APP gene are well-known to be disease-causing. This led Jonnson and colleagues to search for additional rare variants in the APP gene that might be associated with further cases of Alzheimer’s disease. When they analysed their datasets, they stumbled across an associated APP variant. However, this variant does not increase the risk for Alzheimer’s, it reduces it… Continue reading

The Excel contagion

The tale of 16,000 genes. For a recent analysis, I wanted to compile all the gene names of variants that were found in 12 of our EuroEPINOMICS research patients. Since I was planning to do some statistical analysis as well, I used the R package for this, my personal favourite for all kinds of statistics. I also have  weak spot for Minitab and never got along with SPSS, but that is a different story. After I filtered and sorted the genes alphabetically, the following picture made me smile and gave me a reason to write a bit about role of Microsoft Excel for exome analysis…

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When mutations are outside genes: a crime story

CSI Genetics. A headline in the recent issue of Nature Genetics caught my eye the other day: “Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication […]”. Two thoughts went through my head when I read this headline. First, I was wondering how the authors actually found this upstream duplication (one of the last things you look for). Secondly, I realised that demonstrating causality of this duplication must have been very, very difficult. In fact, the paper by Jaeger and colleagues reads like a good detective story and tells several lessons that might apply to EuroEPINOMICSContinue reading

Seizures beget seizures through splicing in flies

The dynamic genome. Up to 95% of human genes undergo a process called alternative splicing. For these genes, several exons are present, which can be used alternatively or can be omitted. Accordingly, a single pre-mRNA can result in a variety of different proteins with different properties. For key players such as voltage-dependent sodium channels, it is therefore interesting to know which role alternative splicing plays in epilepsy. However, the splicing landscape of human sodium channels is complicated and difficult to investigate. Therefore, a model system is required where simple questions can be asked. A recent study now reveals interesting findings related to sodium channel splicing and seizure in the fruit fly.  Continue reading

Charting a bioethical gray zone: genotype-driven research recruitment

The need for re-contact. Genotype-driven research recruitment refers to the inclusion of research participants in future genetic studies based on the findings from previous studies.  For example, deep sequencing efforts within the EuroEPINOMICS Consortium may generate potentially interesting novel variants that warrant further investigation.  In some cases, it might be necessary to obtain more phenotypic information, in other cases, segregation in the family might be of interest.  Since many variants are rare in the general population, genotype-driven approaches are particularly attractive, i.e. research participants are selected based on genetic findings.  This so-called “bottom up” approach allows for targeted studies without the time-consuming and expensive step of re-screening large patient cohorts.  In the future, genotype-driven research efforts will likely become increasingly common, since it is unlikely that large-scale genomic studies alone will be able to sufficiently characterize rare genetic variants.  However, approaching patients based on genetic research data raises important questions. Continue reading