Families. We tend to think that we understand familial epilepsy. The mental image is almost fixed: large pedigrees, clean inheritance, recognizable syndromes, and genes that segregate exactly as expected. But in a recent study from our epilepsy genetics program, we looked at something different. Not discovery cohorts and carefully selected multiplex families, but real-world genetic testing in 484 consecutive families. All families were evaluated in routine clinical care through ENGIN, our Epilepsy Neurogenetics Initiative, which has now evaluated more than 7,000 individuals with epilepsy and related disorders. The result was a picture of familial epilepsy that is both reassuring and unexpectedly complicated. Here is what we found. Continue reading
Tag Archives: DEPDC5
RBFOX3 and the hunt for epilepsy genes in 100,000 genomes
Large scale. Novel epilepsy genes are typically discovered through collaborative studies that combine information across various centers and research groups. However, there are also large-scale sequencing initiatives on a national level that include individuals with epilepsy. In a recent study published in Nature, a wide range of clinical phenotypes were assessed in an initial cohort of 34,000 individuals in the UK 100,000 Genomes Project. Let me dive into the associations related to epilepsy in this publication.
Rewriting the story of neurodevelopmental genes through CNVs in one million people
Copy numbers. When we think about genetic causes of neurodevelopmental disorders and the epilepsies, we typically discuss single genes and de novo variants. Over the last few years, exome and genome data of hundreds of thousands of people have been analyzed, creating large-scale resources to understand genetic variation in health and disease. However, there has been one resource that has always been larger by at least one order of a magnitude – information on copy number variation derived from SNP arrays and array CHG. Now, a recent publication pulls all the existing information together and performs a meta-analysis of rare copy-number variants in nearly one million people. Here is what this study tells us about neurodevelopmental genes and how we can use mismatches between CNV and exome data to answer old questions and find novel genes. Continue reading
Three things I learned about focal epilepsies on the Faroe Islands
Focal to genetic. While there was little interest in the genetics of focal epilepsies only five years ago, the field has gained significant momentum since the discovery of DEPDC5 and the subsequent new appreciation of the mTOR pathway. This finding resulted in several gene discoveries and linked traditional genetic epilepsies with the emerging field of somatic mutations. In May 2017, the European epilepsy genetics community met on the Faroe Islands for the international conference on focal epilepsy. Here are the three things that I learned about focal epilepsies on the Faroe Islands. Continue reading
DEPDC5 – this is what you need to know in 2015
DEPDC5. We have selected DEPDC5 to be our gene of the week. DEPDC5 is currently the most common known gene for focal epilepsies. DEPDC5 mutations cause familial focal epilepsy with variable foci, an epilepsy syndrome with autosomal dominant inheritance where the affected family members can have different types of focal epilepsies, most frequently frontal lobe epilepsy. Despite seizure semiology that varies among family members, it is constant for each individual. Continue reading
Publications of the week: Epilepsiome update, NPRL3, CHD2, and EXT2
Issue 12/2015. This issue of our publications of the week is about two new candidates for familial epilepsies and a study about the phenotypic range of one of our novel epilepsy genes. Also, I wanted to add a brief update on the progress of our Epilepsiome project.
Publications of the week: GRIN2A, SCN8A, and DEPDC5
Issue 10/2015. This week’s publications of the week are about known epilepsy genes that have been around for a while. There are, however, some interesting updates about these genes that are worthwhile discussing. Follow me on a discussion about recent studies on GRIN2A, SCN8A, and DEPDC5. Continue reading
Publications of the week – CNTNAP2, DEPDC5, and autism whole-genome sequencing
Issue 4/2015. Trying to keep up with the publications of the week in the field, we have selected three manuscripts this week, which challenge some of our well-established beliefs. It’s about an autism gene losing its statistical support, a familial epilepsy gene rediscovered in focal cortical dysplasia, and the surprises of whole-genome sequencing in familial autism. Continue reading
Publications of the week – ATK3, TBC1D24, and BRAT1
Getting started in 2015. For the first issue of publications of the week this year, we have chosen a few case reports of genetic epilepsies, which expand the spectrum of known syndromes. All three publications highlight important features of rare genetic epilepsies that you might not have been aware of. Continue reading
A question of conformation – chemical correction of LGI1 dysfunction
ADTLE. Autosomal Lateral Temporal Lobe Epilepsy is a rare monogenic epilepsy that has epileptic seizures with auditory auras as the most impressive feature. This condition is caused in LGI1. In contrast to most other autosomal dominant epilepsies, LGI1 is not an ion channel, but a secreted protein that binds to synaptic cell adhesion proteins. Therefore, the function of LGI1 has always remained slightly mysterious. In a recent publication in Nature Medicine, the functional properties of two LGI1 mutations are modelled in mice. Allowing neurons to secrete altered LGI1 protein otherwise targeted for degradation helped recover some of LGI1’s function. Continue reading