ATP1A3 links alternating hemiplegia of childhood with genetic dystonia and parkinsonism

Alternating Hemiplegia of Childhood (AHC). Acute hemiplegia in children, i.e. weakness of one side of the body, is always a medical emergency. Causes for a sudden hemiplegia can include intracranial bleeds, tumors and rare metabolic disorders. Immediate diagnostic work-up is paramount. In some children, no cause can be found on brain imaging and extensive testing, and the episode remits after hours or days. Strangely, during a following episode, the other side of the body is affected. This condition has been named Alternating Hemiplegia of Childhood (AHC) by Verret and Steele in 1971. AHC is an enigmatic disorder, which is sometimes associated with epilepsy, developmental delay and dystonia. Even though some cases with mutations in SCN1A, CACNA1A, and ATP1A2 have reported, most cases of AHC are unresolved. Given some resemblance with epilepsy and familial hemiplegic migraine, many children with AHC are followed up by epileptologists. The major cause of AHC has now been identified in a recent study… Continue reading

The heritability of schizophrenia, as told by common SNPs

Heritability 2.0. Genome-wide association studies (GWAS) have acquired a slightly negative connotation in the last two years as the results of the enormous efforts were moderate at best. Even though several hundreds of variants have been identified as susceptibility genes for various diseases, the identified genetic risk factors only explain a tiny fraction of the risk for these diseases. Much of what causes common and rare diseases is still unknown – there is a vast discrepancy between population estimates of the genetic contribution and the contribution explained through identified genetic risk factors. This phenomenon has been labeled the “missing heritability”. Now, a recent study using novel statistical tools for GWAS data finds that there is not that much missing after all… Continue reading

Epilepsy genes in noncoding RNA

Genome vs. exome sequencing. Can non-coding regions be skipped in the search for disease-causing variants? Is it worth to pay a higher price for sequencing the whole genome?
The sequencing company Complete Genomics (CGI) is already sounding the death knell for exome sequencing, arguing that the protein-coding genes cover only ~1% of the genome, while many loci identified by GWAS lie in the non-coding regions. CGI maintains that the price difference between whole-genome (WGS) and exome sequencing (ES) has become “less of an issue”. With declining sequencing prices, this will certainly be the case in the future – however, when multiplying the current added costs for WGS with the large numbers of cases and controls required for finding new hits in complex diseases, the proponents of ES have strong arguments. Will WGS explain more than the 10% expected for exome sequencing? Continue reading

Will the relevant SNPs please stand up

The flood of variants.  Every re-sequencing of a genome leads to many more variants than can be validated with functional assays. Many strategies exist to select the candidate variants. Filtering on criteria might remove all variants so efforts are focused to re-rank the list of variants such that the most promising appear on top. A recent review in Nature Reviews Genetics wants to give users a hand with using the bioinformatics tools available. As a bioinformatician, I find a number of important points missing.

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Autism – the shared environment strikes back

Autism and environment. A much talked about recent twin study from California finds a significantly lower heritability in autism than previously estimated, reducing the heritability estimate from >80% to less than 40% and attributing much of the liability of autism to shared, probably prenatal environment. At first, this study may seem to add to the growing pessimism in the genetics field given the lack of explanatory findings from exome sequencing studies. However, things are not that simple and you don’t have to put your exome sequencers on Ebay yet. Also, don’t mention vaccinations again. Let me explain… Continue reading

Conferences on Twitter

Bioinformatics at large. The ISMB conference is a big event and summarizing seven parallel sessions requires additional channels than physical presence. Luckily, there is the Internet. A sufficient number of scientists report of the current session on social media tools like Twitter. In previous years, the conference was supported by FriendFeed but the slow demise of the platform no longer made it possible. Continue reading

Predicting the effects of mutations

From left to right: Sean Mooney, Rachel Karchin, Andre Frank, Shamil Sunyaev, Emidio Capriotti.

How well can we predict the effects of mutations that change the protein sequence? Framed by the the ISMB conference, the largest bioinformatics conference the SNP special interest group met on Saturday the 14th, 2012,  moderated by Emidio Capriotti and Yana Bromberg to discuss current state of the art. Here’s a summary with links a set of tools to try if you study variants.

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Copy numbers, seizures and speech

Why does this child with speech delay get an EEG? My first encounter with Landau-Kleffner-Syndrome and continuous spikes and waves during slow sleep (CSWS) was in medical school when my pediatric neurology attending faced me with this very question. I looked at him and basically had no idea. This is when I learned about the spectrum of rolandic epilepsies and how epilepsy interacts with speech. This concept is best explained by going back to the most common epilepsy in children, Benign Rolandic Epilepsy (BRE). And the genetics of BRE and the rolandic spectrum has been anything else but straightforward. Continue reading

Next Generation Ethics: Struggling with petabyte consent forms

Everyone involved in research with human subjects knows about the importance of informed consent.  The purpose of informed consent is to promote educated decision-making and voluntary participation in research.  Whether or not you’re aware of the fundamental ethical principles underlying the process (patient autonomy and protection from harm, for those keeping score at home), you at least know that you have to get the study participant to sign the form. Continue reading

Of steel mills and exomes – the Luxembourg data analysis meeting

In the shade of the furnaces. The EuroEPINOMICS consortium met for the first data analysis meeting at the Luxembourg Center for System Biomedicine (LCSB) from July 5-7th, 2012. What was intended to be a small, private meeting on data analysis eventually turned into a medium-size consortium meeting with lively, sometimes revealing discussions. Belval is a campus in transition, a large steel mill that is currently transformed into the new campus of the University of Luxembourg. The LCSB people are the “first kids on the block”. The atmosphere of Belval is a mixture of industrial romance and pioneer spirit, the ideal backdrop for re-considering our current approaches to deciphering the genetics of the epilepsies. Continue reading