CHD2 – a 2016 update

Updates. Our “Beyond the Ion Channel” blog has been in existence for over 3 years, during which we have seen many advances in our knowledge of epilepsy genetics and done our best to share them with you. We hope that we have contributed to making epilepsy research more understandable. Recently, we have been pondering what we can do to make the emerging Epilepsiome knowledge base more useful for our readers, including clinicians, researchers, and families alike. Read further to see our first round of changes to our Epilepsiome Gene Pages that we have applied to our CHD2 Gene Page. Continue reading

CHD2 – this is what you need to know in 2015

CHD2. Few genes have captured our attention over the last two years like CHD2 has. It is a gene that we almost missed, then sat on for more than a year since we didn’t believe it, only to realize in the end that it is a gene for a specific photosensitive epilepsy syndrome that many people had encountered, but that few people had a name for. Here is what you need to know about CHD2 in 2015. Continue reading

SCN1A – this is what you should know in 2015

2015 update. Our updates on SCN1A mutations and Dravet Syndrome are amongst our most frequently read posts. Therefore, following the tradition of annual reviews that we started last year, we thought that a quick update on SCN1A would be timely again, building on our previous 2014 update. These are the five things about SCN1A that you should know in 2015. Continue reading

Identifying the Doose gene – SLC6A1 mutations in Myoclonic Astatic Epilepsy

Doose Syndrome. In the early 1970s, a group of children with severe childhood epilepsies was found to have comparable clinical features that consisted of quick jerks and subsequent drop attacks amongst other types of epileptic seizures. These seizures, myoclonic-astatic or myoclonic-atonic seizures, eventually became the defining feature of an epilepsy syndrome referred to as Myoclonic Astatic Epilepsy or Doose Syndrome. In the recent issue of the American Journal of Human Genetics, we report on the first true gene for Doose Syndrome. Here is the story of SLC6A1 (GAT-1). Continue reading

Cause or coincidence – recessive SCN1A variants in Dravet Syndrome

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

Flickering lights, endophenotypes, and EEG genetics – CHD2 in photosensitivity

Heritable. Many epilepsy syndromes have signature EEG traits, and these traits are thought to have a strong genetic component. The endophenotype concept suggests that using these epilepsy-related traits in genetic studies will facilitate gene discovery, a concept that has failed us so far in epilepsy research, unfortunately. Now, in a recent publication in Brain, we were able to demonstrate that variants in CHD2 predispose to photosensitivity, an abnormal cortical response to flickering light. Finally, after several decades of persisting difficulties, there is some progress in the field of EEG genetics. Continue reading

CHD2 myoclonic encephalopathy – delineating a novel disease

CHD2. In 2013, mutations in CHD2 were reported in various publications including two major studies on epileptic encephalopathies, reinforcing the notion that de novo mutations in this gene are a recurrent cause of epileptic encephalopathies. However, large-scale studies often cannot fully appreciate the complete phenotype of the patient behind the gene finding. Therefore, it is difficult to appreciate similarities between patients and assess whether phenotypes constitute a recognizable entity. In a recent publication in Neurology, the phenotype of CHD2 encephalopathy is explored in detail – it represents a distinct, recognizable disease entity. Continue reading

A genetic counselor’s wish list for epilepsy genetics in 2015

Mt. Rainier. After our recent posts about the 2014 AES in Seattle, we received an email from Beth in Boston, highlighting some of the issues that genetic counselor face in epilepsy genetics when dealing with next gen sequencing data. Beth drew up a wish list for 2015 and asked us for comments. Here is a brief discussion between Beth and me on how high throughput epilepsy genetics sometimes comes to grinding halt in clinical practice. Continue reading

Sequencing for developmental disorders on a national level – the DDD(UK) study

DDD. It’s probably the most impressive of all exome sequencing studies of 2014 and I almost missed it. Late December last year, the Deciphering Developmental Disorders study was published in Nature, reporting the genetic findings in more than 1,000 patient-parent trios, which were collected in a systematic nation-wide approach in the United Kingdom and Ireland. The analysis of more than 1,600 de novo mutations in this cohort provides another fascinating view into the genetics of neurodevelopmental disorders, independently confirming the role of DNM1 and pointing out several genes that act through either activating or dominant-negative mutations. Let me guide you through a study that comes to the sobering conclusion that even entire nations are too small to understand the genetics of neurodevelopmental disease. Continue reading