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

GPHN deletions in IGE and mutation-dependent recessive inheritance

Bild1Living in Cologne is a little tough at the moment. Currently, we are in the middle of the Cologne Carnival, the world’s oldest carnival, which started in 1829. Until the upcoming Wednesday the entire city is one big festival. In addition to the 1 million Cologne citizens probably another million tourists will join. Due to this (positive) distraction I will write less than usual. However, I still consider this week’s publications noteworthy. Continue reading

Papers of the week – Encephalitis-antibodies, FAN1, Art and Parent-of-Origin Effects

Dennis' paper of the week

Biggest surprise this week: Imprinted genes interact with non-imprinted genes frequently. But first sequencing reports, statistical frameworks for rare variants analyzes and an impressive translational result.

A novel encephalitis with seizures and the analysis of the effects of antibodies. In their study published in LANCET NEUROLOGY Petit-Pedrol and coworkers characterized serum and CSF samples for antigens in 140 patients with encephalitis, seizures or status epilepticus as well as antibodies to unknown neurophil antigens. High titres of serum and CSF GABAA receptor antibodies are reported to be associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both, which could be exploited for immunotherapy with 15 patients.

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Beneath the surface – the role of small inherited CNVs in autism

Grey zone. Structural genomic variants or copy number variations (CNV) can be reliably assessed using array comparative genomic hybridization (array CGH) or Single Nucleotide Polymorphism (SNP) arrays.  However, for deletions or duplications smaller than 50-100 kB, these technologies have a poor detection rate with many false positive and false negative findings unless platforms are used that target specific candidate regions. Exome analysis, on the other hand, is capable of assessing genetic variation reliably on the single base-pair level. Between both technologies, there is a grey zone of structural genomic variants that are difficult to detect; CNVs smaller than 50 kB are often difficult to assess, and the extent and pathogenic role of these small CNVs is unclear. Now, a recent paper in the American Journal of Human Genetics manages to detect small CNVs through exome data. Their analysis in patients with autism, parents, and unaffected siblings suggests a contribution of small inherited CNVs to the overall autism risk. Continue reading

Identifying core phenotypes – epilepsy, ID and recurrent microdeletions

Triad. There are three microdeletions in particular that increase the risk for the Idiopathic/Genetic Generalized Epilepsies (IGE/GGE). This triad includes microdeletions at 15q13.3, 16p13.11 and 15q11.2, which are hotspot deletions arising from the particular architecture of the human genome. While the association of these microdeletions with epilepsy and other neurodevelopmental disorders including autism, intellectual disability and schizophrenia is well established, the core phenotype of these variants remains elusive, including the question whether such a core phenotype actually exists. In a recent paper in Neurology, Mullen and collaborators zoom in on a possible core phenotype of these microdeletions. The authors investigate a phenotype in which these microdeletions are particularly enriched: generalized epilepsy with intellectual disability. Continue reading

Traveling beyond the ion channel

A how-to guide. July is going to be a slow month for the EuroEPINOMICS blog. Both Roland and I are going on vacation and we will use this time to migrate the entire blog to a more stable and supported server environment. While this always sounds like a quick thing to do, it involves much testing, experimenting and debating and that’s why the Channelopathist will be closed for the month of July. However, we wanted to use this time to provide our readers with brief instructions on how to navigate this blog and our past entries. Speaking of vacation, how far have you traveled beyond the ion channel? Continue reading

Gephyrin, the inhibitory synapse and pathogenic microdeletions

GABA, postsynaptic. The molecular structure of the postsynapse has long been a mystery. Why do receptors cluster at a particular site and don’t simply float around all over the plasma membrane? The identification of postsynaptic scaffolding proteins answered some of these questions. However, it also became clear that inhibitory synapses are completely different from excitatory synapses. Now, a recent paper in Human Molecular Genetics finds that exonic deletions in gephyrin, the main structural protein of the inhibitory synapse, predispose to various neurodevelopmental disorders. Continue reading

NRXN1 deletions and the double hit hypothesis of idiopathic epilepsy

Old friends. Structural genomic variants or Copy Number Variations (CNVs) play an important role in many neurodevelopmental disorders including epilepsy, autism, schizophrenia and intellectual disability. Many of the CNVs representing genetic risk factors overlap between these diseases. Now, a recent study in Epilepsia reports on the exon-disrupting deletions in NRXN1 as genetic risk factors for Idiopathic Generalised Epilepsy. NRNX1 deletions were previously reported in several other neurodevelopmental disorders. However, there is an interesting and unanticipated twist to the story. Continue reading

Double Impact

Second hits. Genomic disorders are genetic disorders due to recurrent microdeletions or microduplications, i.e. small losses or gains of genomic material that happen again and again due to existing breakpoints in the human genome. Intriguingly, additional large microdeletions or microduplications can be identified in some patients with genomic disorders. A recent study in the New England Journal of Medicine tries to explain why. Continue reading