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

Three things you didn’t know about epilepsy and genes

Fall colors. Just a brief summary of how this post originated. Eckernförde is a small city north of Kiel and the weekly Sunday destination of my daughter and me because of the wave pool.  This past Sunday, daylight saving and the fact that she didn’t like her dinner had confused the little girl, and we had been awake since 4AM. As a consequence, she fell asleep on the way, and I kept driving to let her sleep. We made it as far as Haddeby, and I used this time to mentally put a post together that I had been planning for some time. These are the three things that are often misunderstood with regards to epilepsy and genes. Continue reading

CHD2 encephalopathy as a novel Dravet-like epilepsy syndrome

Negative for SCN1A. Today the first major paper by the EuroEPINOMICS-RES consortium was published in the American Journal of Human Genetics online. As you might recall from some of our previous posts, RES has worked on gene identification in patients with Dravet Syndrome negative for SCN1A using trio exome sequencing. A significant fraction of patients turned out to be positive for SCN1A with mutations initially missed using conventional sequencing techniques. However, there was also a second gene that we discovered in an initial cohort of patients with SCN1A-negative Dravet Syndrome. This gene was CHD2.  While working on the functional studies in zebrafish, CHD2 was also discovered as a novel gene for epileptic encephalopathies by both Carvill and collaborators and the Epi4K consortium. These parallel discoveries clearly highlight the relevance of this gene in human epilepsy and suggest that CHD2 mutations might be more common than mutations in many of the other candidate genes discovered in the last 12 months. In addition, when looking closer, the phenotype of the patients was not exactly Dravet Syndrome, but might represent a novel fever-related epileptic encephalopathy. Continue reading

The pebbles of Demosthenes, the King’s speech, and the genetics of stuttering

Communication breakdown. The Greek orator Demosthenes was said to treat his speech impediment by talking with pebbles in his mouth and shouting above the roar of the ocean waves. US Vice President Joe Biden, brutally nicknamed Joe Impedimenta in school, worked on his stuttering reading Emerson and Yeats aloud. Hollywood actor Samuel L. Jackson overcame blocks and pauses while talking by interjecting his trade mark profanity. Given the list of famous people who stutter including Isaac Newton, Charles Darwin, and Theodore Roosevelt, I feel in pretty good company. I am a person who stutters myself, even though my speech impediment is currently mild. Stuttering is a neurodevelopmental disorder whose genetic architecture is entirely unexplored on the molecular level but clinically shares resemblance with many other neurodevelopmental disorders that we have written about on this blog. Today is International Stuttering Awareness Day. I have thought back and forth about whether I want to write this post given my personal involvement as a person who stutters and the resulting lack of objectivity. However, I finally decided to do so in order to put stuttering where it belongs – on a research blog about neurogenetics. Continue reading

SpotOn London 2013 – communicating science online

Outreach. SpotOn is a series of community events for the discussion of how science is carried out and communicated online. SpotOn London (November 7-9, 2013) is organized by the Nature Publishing Group and represents the flagship conference of the SpotOn series. SpotOn discussions fall into three broad topic areas – policy, outreach, and tools – and this site collates the conversations and other archive material around all of the events. Within the outreach track, Roland and I will contribute to the session about scientist-to-scientist communication using blogs and other online tools. Here is why this pertains to you: in a semi-strategic last-minute move, we managed to reserve one extra ticket that we would like to give to a young scientist who would like to join us in London. Short notice? Spontaneous ideas are sometimes the best ideas. Also, for everybody else, there is one last chance on Friday at 12:00 London time to get tickets. Continue reading

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

Relationship quality equals bandwidth – a love letter to my wife

Transatlanticism. This is the 165th post on this blog. My wife Katie read every single one of them, correcting my Denglish phrases, adding Oxford commas, and giving me valuable feedback from her unique perspective as a certified genetic counselor with a research background in epilepsy genetics. Today is Katie’s birthday, and I would like to dedicate this post to her by saying thank you and I love you. Katie and I met at the Epilepsy Research Centre in Melbourne, Australia. In 2007, while driving around Lake Alexandrina in South Australia on a road trip, we listened to Transatlanticism by Death Cab for Cutie. This song became emblematic of our relationship for the years to come while we maintained a long-distance relationship between the US (Katie’s Masters in genetic counseling) and Germany (my residency in Kiel). In 2009, after two years of living on different continents, we were finally reunited. If you were to ask me about the main lesson I took away from this time apart, I would sum this up in a single sentence: “Relationship quality equals bandwidth”. This post is a reflection on why quality matters in the communication between geographically separated individuals. It won’t be a purely romantic post. That’s not my style, and that’s ok with Katie – she has corrected this post, as well. Continue reading

C6orf70, neuronal migration and periventricular heterotopia

Radial migration. The fact that neurons find their place in the cortex during development is nothing short of a miracle. Many neurons originate in the subventricular zone, i.e. the area lining the ventricles. During brain development, these neurons subsequently climb outwards to their final positions using radial glia cells as scaffolds. If this delicate process is disturbed, neurons may be misplaced. Periventricular nodular heterotopia (PVNH) is a condition in which defects in neuronal migration result in ectopic neuronal nodules lining the ventricles. These nodules may result in a broad range of epilepsies, ranging from mild seizure disorders to intractable epilepsy with intellectual disability. Many cases of PVNH are assumed to be genetic, and FLNA and ARFGEF2 as known causative genes. However, the cause remains unknown in a significant number of patients. In a recent paper in Brain, C6orf70 is identified as a new candidate for PVNH using a clever combination of array CGH and exome sequencing. Continue reading

Mutation intolerance – why some genes withstand mutations and others don’t

The river of genetic variants. The era of high-throughput sequencing has given us several unexpected insights into the human genome. One of these insights is the observation that mutations or variations can occur in parts of our genome without any major consequences. Every individual is a “knockout” for at least two genes in the human genome. This means that in every individual, both copies of a single gene are disrupted through mutations or small deletions or duplications. In addition, there are dozens, if not hundreds, of genes with disruptive mutations that affect only a single copy of the gene. Similar mutations in specific disease-associated genes, however, will invariably result in an early onset genetic disorder. This comparison already shows that the genes in the human genome differ with respect to the amount of disruptive genetic variation they can tolerate. A recent study in PLOS Genetics now tries to catalogue the genes in the human genome by assessing their mutation intolerance based on the genetic variation seen in large-scale exome datasets. Many genes for neurodevelopmental disorders are highly intolerant to mutations. Furthermore, some genes for monogenic epilepsies show surprising results in this assessment. Continue reading