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
Category Archives: Bioinformatics
Sequencing for developmental disorders on a national level – the DDD(UK) study
DDD. It’s probably the most impressive of all exome sequencing studies of 2014 and I almost missed it. Late December last year, the Deciphering Developmental Disorders study was published in Nature, reporting the genetic findings in more than 1,000 patient-parent trios, which were collected in a systematic nation-wide approach in the United Kingdom and Ireland. The analysis of more than 1,600 de novo mutations in this cohort provides another fascinating view into the genetics of neurodevelopmental disorders, independently confirming the role of DNM1 and pointing out several genes that act through either activating or dominant-negative mutations. Let me guide you through a study that comes to the sobering conclusion that even entire nations are too small to understand the genetics of neurodevelopmental disease. Continue reading
Beyond the Ion Channel – and back
Where do all the ion channels come from? I would like to start off with a brief commentary about the current state of gene discovery in human epilepsy. Some of our readers rightfully took offense to my previous statement that gene discovery in epilepsy it over – quite the contrary is true, and I apologize for any confusion that I may have caused. Gene discovery in epilepsy is one of the few areas of human genetics with an ongoing, rapid sequence of gene discovery with a tremendous translational potential. But we also need to reconsider the name of this blog – we are far from being beyond the ion channel. The ion channel concept has made a remarkable return in human epilepsy genetics. Let’s find out why. Continue reading
Beyond recessive – KCNC1 mutations in progressive myoclonus epilepsy
PME. The progressive myoclonus epilepsies (PME) are a particular subtype of seizure disorders characterized by progressive myoclonus, generalized seizures and cognitive deterioration. Known causes of PME include recessive mutations in several well-known genes, but the genetic cause is unknown in a significant proportion of patients. Now, in a recent paper in Nature Genetics, de novo mutations in KCNC1 are identified as a novel cause of progressive myoclonus epilepsies. In addition to elucidating the genetic basis in a significant subset of patients with PME, the authors demonstrate that de novo mutations play an important role in a group of diseases usually thought to be recessive. Continue reading
What is the genomic blind spot?
Beneath the surface. Even though the comprehensiveness of next generation sequencing technologies may suggest that we can capture all the variation in the human genome, there is an entire gray zone of small rearrangements that current technologies are blind to. In a recent publication in the American Journal of Human Genetics, Brand and collaborators now use a novel technology to explore the twilight zone of genomics, the realm of small deletions, duplication, inversions and cryptic complex rearrangements. Continue reading
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 five critical components of a clinical exome team
Fall break. Before our blog will go on a two week hiatus, I wanted to share some ideas with you on the team it takes to get a clinical exome analyzed – my impression is that you need at least different five people to translate genomics into patient care. Continue reading
The day I fell in love with Varbank
De novo. Three months ago, I performed a trio exome de novo analysis in a patient-parent trio. From my iPad, in a hotel room in Paris. When I got home a few days later, I was excited to tell my students that the analysis worked. They looked at me slightly confused: “What’s the big deal? We had the analysis complete already a week or so ago.” Last year at this time, I was proud that our lab had established a fully functional de novo analysis pipeline. Suddenly, it’s not a big deal anymore. What happened? Let me tell you about Varbank. Continue reading
How to find recessive disease genes for epileptic encephalopathies
The E2 story continues. There has been major progress in identifying the role of de novo mutations in infantile spasms and other epileptic encephalopathies. Over the last two years, more than 20 new genes for epileptic encephalopathies were discovered and we have good evidence suggesting that de novo mutations play a major role in these disorders. Moreover, we have gotten a good sense on how complicated it can be to call a de novo mutation pathogenic given the flood of rare genetic variants in the human genome. However, de novo mutations are not what we think about clinically when assessing a patient with new-onset epileptic encephalopathy. In a clinical setting, we are often concerned about underlying metabolic disorders, many of which are recessive. Accordingly, we felt that the next task of the E2 consortium was to assess the role of inherited variants in epileptic encephalopathies. Just to tell you in advance, it is not as easy as it sounds.
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
