Living in a post-linkage world, craving knowledge

Genomics meets linkage. This blog post is about family studies in epilepsy genetics. One of my tasks for the next two months is to write the “Trilateral Grant” – we were invited to submit a full proposal for a German-Israeli-Palestinian grant by the German Research Foundation (DFG) on the genetics of familial epilepsies. As keeping up our blogging schedule will be my other big task for the coming months, I thought that I could combine both and explore some topics regarding family studies on this blog. Let’s start with a sobering fact – small dominant families remain difficult to solve, not because of too little but rather too much genetic data. Continue reading

The genetic architecture toolkit – modeling polygenic disease with rare variants

Architecture. Even though we often write about novel gene findings in the epilepsies, we assume that most epilepsies are complex genetic or polygenic. Polygenic inheritance suggests the genetic architecture is composed of multiple interacting genetic risk factors, each contributing a small proportion to the disease risk. However, when using the phrase genetic architecture, sometimes I am not quite sure what I actually mean by this. For example, how many genes are needed? This is why I wanted to build a model genetic architecture and explore what happens if we build a genetic disease solely from rare risk variants. Follow me to a brief back-of-the-envelope calculation of how this might work.

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

G proteins, GNAO1 mutations and Ohtahara Syndrome

G proteins. Intracellular signaling in neurons can occur through various mechanisms including so-called second messengers. G proteins constitute an important part of the signaling cascade that translates the signal from membrane-bound receptors. On neurons, GABA-B receptors or alpha-2 adrenergic receptors use signal transduction through the so-called G alpha-o proteins, which are particularly abundant in the CNS and encoded by the GNAO1 gene. Now a recent paper in the American Journal of Human Genetics describes de novo mutations in Ohtahara Syndrome and movement disorders. Continue reading

Reinventing a consortium – the RES data sharing policy

Share or be shared. During the last two weeks, the RES consortium has approved a new data sharing policy that will allow us to work with increased transparency and accountability within our upcoming projects. This new data sharing policy is a consequent extension of the previous protocols we had in earlier consortia – with one major difference. This time, it’s in writing. While we are getting ready to tackle the large dataset on epileptic encephalopathies released by the Sanger Institute, we took a moment to talk about how things should be running.

Continue reading

16p13.11 microdeletions and the male bias

The enigmatic deletion. Amongst the various microdeletions implicated in human epilepsy, the 16q13.11 microdeletion is one of the structural variations that poses significant difficulties in understanding its associated risk and phenotypes. Now a recent paper in PLOS One investigates a large cohort of patients with various neurodevelopmental disorders for microdeletions in the 16p13.11 region. And particularly the finding regarding the sex distribution of symptomatic deletion carriers is remarkable.   Continue reading

Recessive mutations in autism – the return of hidden metabolic disorders

My wrong guesses of 2012. Two weeks ago during a presentation, I had to admit that there is little evidence for a large contribution of recessive or compound heterozygous mutations in epileptic encephalopathies. At the beginning of 2012, I had initially suggested that recessive or compound heterozygous mutation of known neurometabolic disorders could be identified through exome sequencing in sporadic epileptic encephalopathies. However, as of 2013, there is little evidence for this in our data or the data from other consortia. Now, two papers in Cell suggest a significant contribution of recessive mutations in autism including a revival of the “hidden neurometabolic hypothesis”. Continue reading

The RES-experiments: what results can be expected

Now the experiments to find de novo variants for epileptic encephalopathies within the Euroepinomics RES-project are well underway and first data are coming out, it is a good moment to pause and think about what results we can expect, and how these should be interpreted. For this it is very nice that recent large experiments in autism have provided so much useful data. In this post, I will explore what we can expect in experiments in which we perform whole exome sequencing in a group of patients and their parents to identify de novo variants that could be the cause of the disorder.

Continue reading

Exome study in IGE questions channelopathy concept

IGE and the hunt for rare variants. Idiopathic Generalized Epilepsy (IGE) or Genetic Generalized Epilepsy (GGE) is one of the most common epilepsy subtypes. Family studies and twin studies suggest that genetic factors play an important role. Some families with mutations in GABRG2, GABRA1 and EFHC1 are known, and recurrent microdeletions are found in 3% of sporadic patients. For the majority of patients, the genetic basis remains unknown, but a heterogeneous pattern of rare variants is expected. Much effort is currently spent on genetic studies in IGE including the EuroEPINOMICS CoGIE study. A recent paper now reports the first exome sequencing in IGE to identify rare variants…

Continue reading

Exomes to the extreme to identify modifier gene in cystic fibrosis

Monogenic modifiers. Exome sequencing is a well established method to find causative genes in monogenic disorders, with probably more than 100 genes identified through this method in the last two years. In contrast to the ever-expanding list of monogenic diseases solved through massive parallel sequencing, there is widespread skepticism regarding its usefulness in complex genetic disorders. Now, a recent study in Nature Genetics suggests another application for exome sequencing, the identification of modifier genes in monogenic disorders. Continue reading