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 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

Critical brain-expressed exons and de novo mutations in autism

Selection. De novo mutations in neurodevelopmental disorders including autism, schizophrenia, and intellectual disability raise an important question: are the mutations identified in patients pathogenic or are they simply genomic noise? A recent study in Nature Genetics tries to answer this question by looking at expression of particular exons in the brain and the overall mutational burden in these exons. They come up with critical exons, which seem to be particularly vulnerable in Autism Spectrum Disorder. Continue reading

CACNA2D2, the ducky mouse, and what it takes to be an epilepsy gene

Subunit. Spontaneous mouse mutants help to identify candidate genes for disease mechanisms and have hinted at an important role for ion channels in epilepsy long before the first human channelopathies were identified. The ducky mouse has absence seizures and suffers from ataxia. A truncation mutation in CACNA2D2 could be identified in this phenotype, encoding for an auxiliary calcium channel subunit. This finding emphasizes the role of calcium channels in absence seizures and begs the question whether genetic variation in CACNA2D2 is also involved in human epilepsy. A recent publication in PLOS One now identifies the second recessive CACNA2D2 mutation in a patient with epileptic encephalopathy. But are two independent cases sufficient anymore to claim causality? Continue reading

Navigating the epilepsiome – live from Tübingen

2D. I am writing this post during our EuroEPINOMICS meeting in Tübingen listening to presentation from CoGIE, the EuroEPINOMICS project working on IGE/GGE and Rolandic Epilepsies and RES, the project on rare epilepsies. At some point during the afternoon, I made my selection for the best graph during the presentations today – an overview of the conservation space of epilepsy genes. Continue reading