Recessive epilepsies. Dravet Syndrome is one of the most prominent genetic epilepsies and presents in the first year of life with prolonged fever-associated seizures. Haploinsufficiency of SCN1A, either through mutations or deletions, is the major cause of Dravet Syndrome. In a recent publication in the European Journal of Pediatric Neurology, two families with recessive Dravet Syndrome and biallelic SCN1A variants are reported. Let’s have a look at how to interpret these findings. Continue reading
Tag Archives: SCN2A
EFHC1 – retiring an epilepsy gene
The era of gene retirement. As of 2015, the list of epilepsy genes has shrunk by one. EFHC1, a gene initially proposed to be a monogenic cause of Juvenile Myoclonic Epilepsy, is no longer an epilepsy gene. A recent study in Epilepsia finds that EFHC1 variants initially thought to be pathogenic are found in unaffected controls of the same ancestry. Follow us on one of the most perplexing journeys that modern day neurogenetics has to offer, and the retirement of the first epilepsy gene. Continue reading
SCN8A encephalopathy – and how it differs from Dravet Syndrome
Nav1.6. For some reason, SCN8A always met some resistance. In contrast to other epilepsy genes, it took a while for the community to embrace this gene as a genuine cause of epileptic encephalopathies. A recent publication in Neurology now investigates the phenotypic spectrum of SCN8A encephalopathy – and points out important features that distinguish this condition from Dravet Syndrome. Continue reading
TADA – a joint analysis of de novo and inherited risk factors in autism
Beyond de novo. One of the most robust ways to interpret exome data is the analysis of de novo mutations. However, in addition to the 1-2 de novo events that we can identify in every individual, there is a plethora of inherited variants that often look suspicious. Unfortunately, other than looking at monogenic recessive disorders, we are often incapable of understanding the importance of these inherited variants and tend to ignore them. A recent publication in Nature now overcomes this difficulty by applying a joint analysis of inherited and de novo variants in autism. Continue reading
These are the top 10 epilepsy genes of 2014
Top 10. 2014 has been a very productive year in epilepsy gene discovery and with our final blog post this year, we wanted to provide a brief overview of what has been pertinent this year. From the multitude of novel genes identified this year, here are the 10 most relevant findings – including some genes that you probably didn’t expect. Continue reading
Here are five AES abstracts you should know about
Summary. The 68th Annual Meeting of the American Epilepsy Society is now over and I would like to use this opportunity to look at five epilepsy genetics posters that caught our attention. The genetics posters at AES this year were a mixture of expansion of known phenotypes and some novel genes that might be worth looking at. Continue reading
Beyond the Ion Channel – and back
Where do all the ion channels come from? I would like to start off with a brief commentary about the current state of gene discovery in human epilepsy. Some of our readers rightfully took offense to my previous statement that gene discovery in epilepsy it over – quite the contrary is true, and I apologize for any confusion that I may have caused. Gene discovery in epilepsy is one of the few areas of human genetics with an ongoing, rapid sequence of gene discovery with a tremendous translational potential. But we also need to reconsider the name of this blog – we are far from being beyond the ion channel. The ion channel concept has made a remarkable return in human epilepsy genetics. Let’s find out why. Continue reading
From zero to one hundred in the genetics of Febrile Seizures
Finally. Only a few months ago, we wondered what happened to the genetics of Febrile Seizures, given that there was a paucity of publications in this field. Now, a recent publication in Nature Genetics presents the first well-powered genome-wide association study in Febrile Seizures in almost 2,000 patients, including a large subgroup of patients with Febrile Seizures after MMR vaccinations. The authors provide compelling evidence for common variants in known epilepsy genes. However, the strongest genetic risk for Febrile Seizures is in a known disease gene that nobody expected. Continue reading
SETBP1, ZMYND11, and the power of joint exome and CNV analysis
Parallel worlds. There are two fields of genetics for neurodevelopmental disorders that currently produce large amounts of data – the field of copy number variation analysis and the field of exome sequencing. When assigning pathogenicity, information from both genetic technologies are rarely considered jointly. A recent study in Nature Genetics now performs a combined analysis of a large CNV and exome datasets in intellectual disability and autism. Interestingly, this method produces robust results, highlighting novel causative genes. Continue reading
Dynamin 1, the synapse, and why epilepsy gene discovery is now officially over
E2 consortium. Infantile Spasms and Lennox-Gastaut Syndrome are two epilepsy syndromes with a strong genetic component. De novo mutations play an important role in genetic epilepsies. However, given the overall mutational noise in the human genome, telling causative genes from innocent bystanders is difficult. In the largest and most comprehensive analysis so far, our E2 consortium just published a joint analysis of 356 patient-parent trios, which were analyzed by exome sequencing. In addition to implicating DNM1, GABBR2, FASN, and RYR3, this publication sends a clear message: the age of gene discovery in epilepsy is over – from now on, genes will find themselves. Let me tell you what I mean by this. Continue reading