Recessive mutations in autism – the return of hidden metabolic disorders

My wrong guesses of 2012. Two weeks ago during a presentation, I had to admit that there is little evidence for a large contribution of recessive or compound heterozygous mutations in epileptic encephalopathies. At the beginning of 2012, I had initially suggested that recessive or compound heterozygous mutation of known neurometabolic disorders could be identified through exome sequencing in sporadic epileptic encephalopathies. However, as of 2013, there is little evidence for this in our data or the data from other consortia. Now, two papers in Cell suggest a significant contribution of recessive mutations in autism including a revival of the “hidden neurometabolic hypothesis”. Continue reading

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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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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Exomes to the extreme to identify modifier gene in cystic fibrosis

Monogenic modifiers. Exome sequencing is a well established method to find causative genes in monogenic disorders, with probably more than 100 genes identified through this method in the last two years. In contrast to the ever-expanding list of monogenic diseases solved through massive parallel sequencing, there is widespread skepticism regarding its usefulness in complex genetic disorders. Now, a recent study in Nature Genetics suggests another application for exome sequencing, the identification of modifier genes in monogenic disorders. 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

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

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

Gene birth in yeast and human

The completion of the human genome came with few surprises it seems in retrospect. One was the observation that the human genome apparently had much fewer genes than  expected. I never understood the fuss that was made about the total gene number, as referring to an absolute number of genes is a gross simplification of the facts. How many genes we have is highly dependent on what we call a gene and how we identify them in the human genome. When talking about the total number of genes, how can you leave out all the problems of probabilistic algorithms for gene identification and the difficulties of proving gene expression and coding potential experimentally? Continue reading

Why CNS disorders are more likely to be monogenic

Once again, the flood of rare variants. Deep sequencing studies have revealed an unexpected plethora of rare variants, i.e. genetic variants that can only be found in few or even single individuals. While the genetic architecture of more common genetic variants, so-called Single Nucleotide Polymorphisms (SNPs) is well known through the HapMap project, the role of rare variants identified with recent sequencing studies is difficult to interpret. Basically, for an individual variant it is difficult to establish whether this variant is disease-causing or disease-related based on the frequency in cases. Establishing association at the same level of statistical significance as required for SNPs is difficult given that much larger samples are needed. Furthermore, protein prediction algorithms have their limitations and might not be able to discriminate an accidental from a causal variant, given that every individual might be homozygous or compound homozygous for gene-disrupting variants in at least three genes. We are drowning in a flood of rare variants and cannot distinguish pathological from benign variants very well yet. Continue reading

Old friends

The functional interactions of two genes can be predicted by their conserved proximity in the genomes of distant species. The observation can be used to build large scale networks for bacterial species e.g. in the STRING database but there is little evidence for such conservation in larger eukaryotic species such as animals. Metazoan gene order is scrambled after short periods of evolutionary time and few interactions can be found except for the conserved Hox gene clusters.

Gene-gene pairs in metazoan genomes. Irimia et al. now show the prediction of 600 gene-gene interactions in human and more in other species by analysis of conservation across 17 metazoan genomes and demonstrate the validity by a variety of large scale experiments. In brief, some gene-gene-pairs are more conserved than expected, suggesting a functional relationship. Not all gene pairs are adjacent – longer range interactions are also studied.  It’s funny to read such a seemingly simple analysis in 2012 as so many people will have tried similar lines of research after the observations by Abachi and Lieber about bidirectional promoters, i.e. promotors, which affect gene expression in the upstream and downstream direction. The small number of available metazoan genomes might have been a cause for the late discovery. Or am I expecting science to move too fast?

Adachi and Lieber found that bi-directional gene pairs are conserved in higher eukaryotes and suggest the accepted explanation that a single promoter drives the expression of both genes.

Location, location, location. The number of new interactions identified by Irimia et al. is small but the experimental data lined up supposedly point towards high degree of true positives. The identified genes might not be of direct interest to epilepsy genetics as they are primarily found it basic cellular functions. But the observation that conservation is strong on a few gene pairs hopefully allows a glimpse on what shapes the genetic architecture, suggesting other neighbouring genes in humans might have positional effects. A recent publication by Campbell et al. provides an interesting example for epilepsy research and suggests cis-regulatory effects between epilepsy genes at the chromosomal region 9q34 including STXBP1 and SPTAN1. I wonder what role non-coding RNAs play in the cases presented by Irimia et al., which is not touched upon.