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
Category Archives: Epileptic encephalopathy
Beyond recessive – KCNC1 mutations in progressive myoclonus epilepsy
PME. The progressive myoclonus epilepsies (PME) are a particular subtype of seizure disorders characterized by progressive myoclonus, generalized seizures and cognitive deterioration. Known causes of PME include recessive mutations in several well-known genes, but the genetic cause is unknown in a significant proportion of patients. Now, in a recent paper in Nature Genetics, de novo mutations in KCNC1 are identified as a novel cause of progressive myoclonus epilepsies. In addition to elucidating the genetic basis in a significant subset of patients with PME, the authors demonstrate that de novo mutations play an important role in a group of diseases usually thought to be recessive. Continue reading
Heat at the synapse – STX1B mutations in fever-associated epilepsies
Febrile Seizures. The discovery of the genes for fever-associated epilepsies was one of the most relevant milestones in epilepsy genetics. Discovery of the underlying genes including SCN1A, SCN1B and GABRG2 was tightly linked to the development of the Genetic/Generalized Epilepsy with Febrile Seizures Plus (GEFS+) concept, describing the spectrum of epilepsy phenotypes seen in families with these mutations. Gene discovery in GEFS+, however, has slowed down in recent years, and no further causative genes had been identified for more than a decade. Now, in a recent paper in Nature Genetics, mutations in STX1B are found as a novel cause for fever-associated epilepsies. Continue reading
PURA mutations and when diverse phenotypes become a single syndrome
Reverse. With the increasing amount of genetic information available in patients with various neurodevelopmental syndromes, some genes will be observed more than once in patients. In a recent study in the Journal of Medical Genetics, the authors trace back the phenotypes of individuals carrying de novo mutations in PURA. However, there seems to be a wide range of clinical features with a seemingly inverse genotype-phenotype correlation. 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
The five critical components of a clinical exome team
Fall break. Before our blog will go on a two week hiatus, I wanted to share some ideas with you on the team it takes to get a clinical exome analyzed – my impression is that you need at least different five people to translate genomics into patient care. Continue reading
Publications and thoughts of the week – SUMO, SENP2, and data return from exome studies
This week. Because I was traveling this week, I didn’t manage to put a blog post together for you. However, I wanted to catch up with recent publications in the field. Also, I wanted to point out a recent trend in the field – emerging interest and concern about data return from next-generation sequencing studies. However, let’s start with this week’s publications. Continue reading
Three reasons why exomes are like MRIs – and three reasons why they are not
Exome rounds. How will next-generation sequencing technologies impact on patient care in the future? What role will genetic analyses play in routine health care? Sometimes, the possible role of genetic information is compared to the role of MRI imaging, including the general expertise that is required of clinicians who apply these technologies but are not necessarily dedicated experts in the field. Here are three interesting parallels between exomes and MRI – and three examples how the impact of these technologies differs drastically. Continue reading
The 1003 possible autism genes – a matter of constraint
Overview. There have been numerous publications on de novo mutations in autism and intellectual disability over the last three years. Many of these studies struggle to distinguish signal from noise, and the plethora of findings leaves the reader wondering which genes are bona fide autism genes and in which cases the evidence is limited. A recent paper in Nature Genetics uses a new metric to assess expected versus observed de novo mutations in more than published 1000 autism patient-parent trios – and the answers appear to be straightforward. Continue reading
