The first Online Symposium: Rare Genetic Variants Associated with Neurodevelopmental Disorders

Online. Last week, we held the first online symposium on “Rare Genetic Variants Associated with Neurodevelopmental Disorders”. The meeting covered seven topics which included different genomic approaches used to unravel the genetic architecture of neurodevelopmental disorders and cognitive traits. In total, 117 participants joined the meeting with a peak of 72 participants listening to a presenter. Continue reading

Welcome to Rare Variant Island

Gamification. Genetic epidemiology is probably one of the driest and most boring fields of genome science that you will encounter. However, there are some basic questions that keep on puzzling me. One of them is about rare variants: if we think of rare variants that are present in patients, but also in controls, how could a combination of rare variants ever fully explain a disease? What are the rules, what are the conditions for such a situation? I happened to play around with R yesterday, and caught by a wave of gaming spirit, I wanted to try and see. I created a virtual population with 1 million people where disease risk is almost fully explained by 300 rare variants – a little genetic SimCity that I will call Rare Variant Island. Follow me through some of the adventures in our new empire and see what happens. Continue reading

Remembering the five Ps: how to interpret genetic variants in epilepsy

Epilepsiome. Two weeks ago, we had a few teleconferences about what the purpose of our gene curation and gene review efforts should be. Should we be a blog, should we be OMIM, or should we be a new neuromuscular homepage?  None of these resources feel quite right for the questions that we have in epilepsy genetics. While thinking about this question, it became clear to me that we need to address five different aspects of each epilepsy gene, a framework that I’ll refer to as the 5-P concept. What is this concept about? Follow me onto a journey into the essential dimensions of interpreting the relevance of a variant in a clinical context. Continue reading

Here are 5 quick free web-based tools for gene interpretation

Exome rounds. Interpreting genetic variants is one of the main challenges in genomic medicine. Many people have perceived barriers to starting some of the variant analysis themselves, given that there is the widespread notion that this requires expert bioinformatics knowledge. However, this is somewhat a concept of the past. There are some beautiful and simple tools online that you can use for free. Here are my favorite web-based tools for variant interpretation. Continue reading

Here is why CADD has become the preferred variant annotation tool

Variant annotation. In both clinical practice and within existing research projects, we’re often faced with the issue of telling whether a given variant is benign or whether it is pathogenic. In silico prediction tools are designed to help this decision making process. However, there are so many of them and it is often hard to assess which tool works best. In a 2014 publication in Nature Genetics, the CADD score was introduced as comprehensive tool that aims to take the results of many known prediction tools into account. Follow me on a journey that takes us on hyperplanes, support vector machines and every possible variant in the human genome. Continue reading

Exomes on the go – adventures with wANNOVAR

Going cloud. This post is about my most recent discovery when I was trying to modernize some of the bioinformatics tools that I had on my laptop. My experience with variant annotation is a good example of the latest trend in bioinformatics: replacing precise, but difficult-to-use tools by web-based convenience – I didn’t need to install anything after all. This is a brief journey into the world of variant annotation, taking advantage of my new favorite tool, wANNOVAR and applying it to the Epi4K dataset. Continue reading

Reelin, migration and an unexpected gene for lateral temporal lobe epilepsy

Reeler. In 1951, the geneticist D.S. Falconer identified a spontaneous mouse mutant with an abnormal, “reeling” gait. This mouse, aptly called reeler, was later found to have developmental abnormalities of the cerebellum and, most prominently, an inversion of the layers of the cortex. At this point, interest was piqued to identify the underlying gene, which was eventually pinpointed in 1995. Reelin, the culprit gene, was found to be a secreted protein of cortical support cells and was subsequently found to be the cause of human lissencephaly with cerebellar hypoplasia (LCH). In a recent study in the American Journal of Human Genetics, reelin takes on a new role as a novel gene for a familial form of lateral temporal lobe epilepsy. Continue reading

Salt matters – SIK1 in epileptic encephalopathies

Inducible. Next generation sequencing technologies have the tremendous potential to identify disease-causing genes in a hypothesis-free manner. In a recent publication in the American Journal of Human Genetics, mutations in the gene for the salt-inducible kinase 1 (SIK1) are found in patients with early onset epileptic encephalopathy. In addition to a previously unknown functional network related to intracellular salt in the CNS, the authors demonstrate a peculiar mutational mechanism – activating truncation mutations. 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

Discrepancies in interpretation – when can exomes speak from themselves?

Interpretation. There is huge promise in discovering the genetic basis of neurodevelopmental disorders using exome sequencing, but it is often not clear how ambiguous results are communicated to families. In a recent publication in Clinical Genetics, the authors try to understand what happens to exome results as they land on the clinician’s desk – and leave us with the conclusion that diagnostic exome sequencing when reviewed in a clinical setting may have a false positive rate of up to 20% with 5% of false negatives. Continue reading