De novo mutations in severe intellectual disability

Diagnostic exome sequencing. Severe intellectual disability (ID) is unexplained in the vast majority of patients and is thought to be genetic. The genetics of intellectual disability has traditionally focused on the X chromosome, where more than 100 possibly causative genes for ID are located. But other, autosomal genes are also found in large number of cases. A recent study in the New England Journal of Medicine now reports on trio exome sequencing in patients with unexplained severe intellectual disability. The authors identify causative de novo events in a large proportion of patients. Interestingly, more than half of their patients had epilepsy. Continue reading

Gamification of life science – The CAGI challenge

Everybody wins. The scientific publication process is not ideal to find the best bioinformatics methodology for a given problem. Most predictions are not performed blind as our data sets are so small that separating them in to several disjoints sets for training and testing purposes is not possible or sensible. The structural biology community has started to tackle the problems by establishing a competition called Critical Assessment of protein Structure Prediction (CASP). For example, the solution of the 3D structure of a protein is announced but the data withheld for a couple of months to give computational groups time to submit a prediction which is then evaluated by an independent team. A concluding conferences crowns the best prediction groups. In recent years, systems biology and sequence interpretation produce sufficient data to make similar challenges possible. Continue reading

The London 2012 ECE in retrospect

The Shard. London has changed quite a bit since my last visit and I didn’t really pay that much attention to the Olympics, I must admit. Both became clear to me when I left the train at London Bridge Station. There it stood in front of me: The Shard. London’s new high-rise building, the tallest skyscraper in the European Union. And I had no idea that it even existed. On a smaller scale, there were also a few surprises for me at the ECE in the world of epilepsy genetics. Continue reading

The rise of the Channelopathist

Gotham City. Strange sightings have recently occurred in EuroEPINOMICS land. Scientific evildoers and exomic villains tremble in fear. The field respectfully speaks of a masked superhero roaming the floors of major genome centers. His superpowers appear beyond description. Witness the rise of the Channelopathist – and a slightly unusual blog post on epilepsy genetics. Continue reading

Exome shock with acute in-house deficiency

Sleep disturbances, double vision, writer’s cramp. As some of you might recall, I was not fully conscious during our Young Investigator’s meeting two weeks ago, spending most of the time in a haze either hacking random commands into my laptop with sweaty palms or desperately trying to communicate with my neighbor in Unix, Perl or Loglan. Ever since then, people have remarked that I have lost weight and that I haven’t smiled since. What has gotten a hold of me? It all started out with a small, innocent hard drive that made its way from Antwerp to Kiel. 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

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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Exome study in IGE questions channelopathy concept

IGE and the hunt for rare variants. Idiopathic Generalized Epilepsy (IGE) or Genetic Generalized Epilepsy (GGE) is one of the most common epilepsy subtypes. Family studies and twin studies suggest that genetic factors play an important role. Some families with mutations in GABRG2, GABRA1 and EFHC1 are known, and recurrent microdeletions are found in 3% of sporadic patients. For the majority of patients, the genetic basis remains unknown, but a heterogeneous pattern of rare variants is expected. Much effort is currently spent on genetic studies in IGE including the EuroEPINOMICS CoGIE study. A recent paper now reports the first exome sequencing in IGE to identify rare variants…

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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

FAME – when phenotypes cross over but chromosomes don’t

Crompton and colleagues recently published the clinical and genetic description of a large family with Familial Adult Myoclonic Epilepsy (FAME).  This phenotype is particularly interesting since it provides some insight into how neurologists conceptualize twitches and jerks.  It is also a good example that large families do not necessarily result in a narrow linkage region, particularly when centromeric regions are involved.

What is myoclonus?  Despite usually mentioned in the context of epilepsy, most people are inherently familiar with myoclonus. Most of us “twitch” when we fall asleep and sometimes experience this twitch as part of a dream.  These episodes are entirely normal and are called hypnic jerks, but they give people a good idea of what a sudden, brief, shocklike, involuntary movement caused by muscular contraction or inhibition would feel like.  Myoclonus in the setting of epilepsy is usually mentioned as part of a Juvenile Myoclonic Epilepsy (JME) or Progressive Myoclonus Epilepsy (PME).  Please note that both epilepsies use different endings to describe the twitch (“-us” vs. “–ic”).  This is mainly convention.  Basically, myoclonus is a brief shock-like twitch, which can affect almost every part of the body and can be due to dysfunctions in various regions in the Central Nervous System.

The neuroanatomy of twitching.  A motor command from the cerebral cortex has to pass through several steps prior to execution.  For example, the simple command of tapping a finger on the table surface is prepared by the cortex through several loops before being sent down your spine.  Accordingly, myoclonus can arise from different parts in the brain.  (1) The cortical myoclonus is due to a purely cortical source and can be seen in many forms of symptomatic myoclonus.  (2) The cortico-subcortical myoclonus is due to feedback from the cortex to other brain areas. This is the myoclonus we see in patients with JME.  Both variants may be seen on EEG since the cortex is involved.  (3) The subcortical-supraspinal myoclonus is generated in the brain stem or below and is responsible for phenomena such as hyperekplexia or startle disease.   Some forms of hyperekplexia, literally “exaggerated surprise”, are due to mutations in genes involved in glycinergic transmission and can be found in some isolated communities such as the Jumping Frenchmen of Maine.  (4) Finally, there is also spinal and peripheral myoclonus.

FAME – epilepsy or movement disorder?  Familial Adult Myoclonic Epilepsy (FAME) is an enigmatic familial disorder with the triad of myoclonus, tremor and seizures.  Several families have been described and two loci on 8q23.3-8q24.11 and 2p11.1-q212.2 for FAME have been established.  The underlying genes are still unknown.  Crompton and colleagues no describe a large six-generation family with FAME in Australia/New Zealand.  The familial disease usually starts with tremor in early adulthood in the affected family members, even though a wide range of age of onset is observed. Interestingly, only a quarter of all affected family members had seizures, which is in contrast to previous studies.  Therefore, FAME may actually be better characterized as a movement disorder with concomitant seizures rather than a familial epilepsy syndrome.  The authors also point out the difficulties distinguishing FAME from the much more common essential tremor (ET).  In particular, the well-described response to β-blockers seen in patients with ET can also be observed in some family members.

Figure 1. The candidate gene landscape of the chr2 FAME region. All genes were searched for the number of hits in PubMed for the listed search terms in an automated fashion. As usual in large linkage intervals, only few genes are known in the context of neurological disorders, while most genes are unknown.

The genetics of FAME.  Crossovers during meiosis usually lead to a progressive narrowing of the linkage interval in familial disorders.  However, the lack of crossover events leads to very large linkage intervals even in very extended families.  The family described by Crompton et al. links to the pericentromeric region of chromosome 2.  Pericentromeric regions usually have a low frequency of crossover events, and this phenomenon has also delayed the identification of other familial epilepsies such as Benign Familial Infantile Seizures with mutations in PRRT2.  The linkage region contains almost 100 genes and Figure 1 shows the “candidate gene landscape” in this region.  While some genes clearly classify as top candidate genes, the majority of the genes in this region are unknown in the context of epilepsy. Therefore, identification of the FAME gene will be exciting and provide us with novel insight on how genetic alterations may produce combined neurological phenotypes.