EIEE1-19. Online Mendelian Inheritance in Man (OMIM) is one of the most frequently accessed online databases for information on genetic disorders. Genes for epileptic encephalopathies are organized within a phenotypic series entitled Early Infantile Epileptic Encephalopathy (EIEE). The EIEE phenotypic series currently lists 19 genes (EIEE1-19). Let’s review the evidence for these genes as of 2014. Continue reading
A growing number of genes have been identified to be causative for genetic forms of epilepsy, which are neither ion channels, receptors nor other classical epilepsy genes but epigenetic players. The epigenetic enzymes and effector proteins described to be mutated in inherited genetic epilepsies as well as epileptic encephalopathies, intellectual disability syndromes and autism spectrum disorders with associated severe or occasional seizure phenotype are of various function. Since this function never seems to be sufficiently discussed in the respective publications and little is to be found on how these genes may be linked to the phenotype, here comes a little overview summarizing how epigenetics is contributing not only to symptomatic focal epilepsy but may also help to explain the phenotypic heterogeneity of genetic epilepsies.
The river of genetic variants. The era of high-throughput sequencing has given us several unexpected insights into the human genome. One of these insights is the observation that mutations or variations can occur in parts of our genome without any major consequences. Every individual is a “knockout” for at least two genes in the human genome. This means that in every individual, both copies of a single gene are disrupted through mutations or small deletions or duplications. In addition, there are dozens, if not hundreds, of genes with disruptive mutations that affect only a single copy of the gene. Similar mutations in specific disease-associated genes, however, will invariably result in an early onset genetic disorder. This comparison already shows that the genes in the human genome differ with respect to the amount of disruptive genetic variation they can tolerate. A recent study in PLOS Genetics now tries to catalogue the genes in the human genome by assessing their mutation intolerance based on the genetic variation seen in large-scale exome datasets. Many genes for neurodevelopmental disorders are highly intolerant to mutations. Furthermore, some genes for monogenic epilepsies show surprising results in this assessment. Continue reading
The de novo paradigm. De novo mutations play a significant role in many neurodevelopmental disorders including autism, intellectual disability and schizophrenia. In addition, several smaller studies have indicated a role for de novo mutations in severe epilepsies. However, unless known genes for human epilepsies are involved, findings from large-scale genetic studies are difficult to interpret. De novo mutations are also seen in unaffected individuals and only very few genes are observed more than once. Now, a publication in Nature by the Epi4K and EPGP collaborators uses a novel framework to tell pathogenic mutations from genomic noise. Their study provides very strong evidence for a predominant role of de novo mutations in Infantile Spasms and Lennox-Gastaut Syndrome. Continue reading
Exome no more. Over the last 15 months, we have repeatedly discussed how exome sequencing or genome sequencing is applied to neurodevelopmental disorders in order to discover new candidate genes and to assess the role of known candidate genes. We have also wondered sometimes whether exome sequencing is the most straightforward approach. Now – outpacing the two large international consortia using exome sequencing in epileptic encephalopathies – a recent study in Nature Genetics uses a different approach to uncover the genetic basis in 10% of patients with epileptic encephalopathies. Targeted resequencing or gene panel analysis is a hybrid technology between candidate gene sequencing and next generation sequencing and focuses only on a subset of candidate genes. While their study provides a comprehensive overview over the genetics of rare epilepsy syndromes, it raises the question whether the era of large-scale exome sequencing is coming to a natural end. Continue reading
Trio-sequencing your clinic. From the perspective of a child neurology clinic, I often wonder how much information we would gain if we performed trio exome sequencing for de novo mutations systematically in all our patients with difficult-to-treat epilepsies. Many of these patients have epilepsies that are difficult to classify and they have not been included in our existing EuroEPINOMICS working groups on defined syndromes. Now, a recent publication in Epilepsia gives us an idea what we will find if we perform family-based exome sequencing in patients with unclassified epileptic encephalopathies. Basically, you will find SCN1A and CDKL5 plus mutations in several genes that are likely pathogenic. But there is much more to this issue, which motivated me to come up with a classification scheme for epilepsy-related de novo events. Continue reading
Quantum leap. At the Annual Meeting of the American Epilepsy Society, the Epi4K consortium presented the first data on exome sequencing in epileptic encephalopathies. This data is the most exciting finding in the field of epilepsy genetics in 2012 so far, as it provides a deep insight into the genetic architecture of Infantile Spasms (IS) and Lennox-Gastaut Syndrome (LGS). With the findings presented by the Epi4K collaborators, the epileptic encephalopathies are joining a group of neurodevelopmental disorders with a significant burden of de novo mutations. However, there are important differences that set both IS and LGS apart from diseases like autism, intellectual disability and schizophrenia. Continue reading