SCN1A and Dravet Syndrome – your questions for the Channelopathist

Comments. After posting our 2015 update on what you should know about SCN1A, we received a number of comments on our blog and by email. We usually have the policy to respond to every comment individually. However, after we had realized that we had fallen behind with a few replies for several weeks, we felt that it might be worthwhile rephrasing some of the questions as general topics to write about, especially since many of your questions raised interesting points. Here are the questions that you asked regarding SCN1A and Dravet Syndrome. Continue reading

The microdeletion landscape of Genetic Generalized Epilepsy

CNV. Structural genomic variations or Copy Number Variations (CNVs) significantly contribute to the genetic architecture of many neurodevelopmental disorders. However, given the enormous variation in the human genome in healthy individuals, the precise contribution of CNVs remains poorly understood. In a recent publication in PLOS Genetics, we were able to assess the microdeletion architecture in more than 1,000 patients with Genetic Generalized Epilepsy (GGE) compared to more than 5,000 controls. We found that microdeletions occur almost twice as often in GGE patients compared to controls, an analysis that revealed both known suspects and interesting candidates. 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

The two faces of KCNA2 – a novel epileptic encephalopathy

Delayed rectifier. The discovery of de novo mutations in ion channel genes as a cause for genetic epilepsies continues. In a recent publication in Nature Genetics, we have identified de novo mutations in KCNA2 as a novel cause of epileptic encephalopathies associated with ataxia. Interestingly, even within a single gene, two different phenotypes seem to be emerging. Continue reading

How genome sequencing in intellectual disability breaks the 50% boundary

Exome failures. Trio exome sequencing has the huge potential to discover the genetic basis of neurodevelopmental disorders. However, the results are negative for the majority of patients. In a recent study published in Nature, genome sequencing was applied to exome-negative patients with intellectual disability, identifying mutations in coding regions that were previously missed. But are the authors correct in stating that they can explain more than 60% of cases in an unselected cohort? Continue reading