Trio-sequencing your clinic. From the perspective of a child neurology clinic, I often wonder how much information we would gain if we performed trio exome sequencing for de novo mutations systematically in all our patients with difficult-to-treat epilepsies. Many of these patients have epilepsies that are difficult to classify and they have not been included in our existing EuroEPINOMICS working groups on defined syndromes. Now, a recent publication in Epilepsia gives us an idea what we will find if we perform family-based exome sequencing in patients with unclassified epileptic encephalopathies. Basically, you will find SCN1A and CDKL5 plus mutations in several genes that are likely pathogenic. But there is much more to this issue, which motivated me to come up with a classification scheme for epilepsy-related de novo events. Continue reading
Tag Archives: exome sequencing
Dealing with the genetic incidentaloma – the ACMG recommendations on incidental findings in clinical exome and genome sequencing
Clinical genome sequencing. While exome and genome sequencing is widely used as a research tool, these technologies are also routinely applied in a clinical setting. As with many other data-rich diagnostic tests in medicine, there is an ongoing question on how to deal with potentially relevant findings that turn up indicentally. Now the American College of Medical Genetics and Genomics (ACMG) has released their long-expected recommendations on data return of incidental findings in clinical exome and genome sequencing. Their recommendations provide an interesting basis for discussion on what to do with genetic findings that are found by chance. Continue reading
PGAP2 mutations and intellectual disability with elevated alkaline phosphatase
Red flags. Despite the availability of a large panel of metabolic and genetic tests as well as high-resolution neuroimaging, the cause of disease in the vast majority of patients remains unknown. This situation also applies for intellectual disability, where there is little to offer in terms of diagnostic procedures once patients are negative for array comparative genomic hybridization (array CGH). In clinical practice, we often hope that some minor clinical or biochemical features may lead us to the correct diagnosis, but in the majority of cases, these investigations lead nowhere. Now, in two back-to-back publications in the American Journal of Human Genetics, two papers describe PGAP2 mutations in patients with non-syndromal intellectual disability with elevated alkaline phosphatase. Continue reading
The sequester and biomedical research – lessons for Europe
Transatlantic. The so-called sequester, automatic spending cuts across the board- have gone into effect in the US and also impact on the level of public funding for biomedical research. In a recent commentary in JAMA, Ezekiel Emmanuel comments on the decline of support for the NIH, which he believes goes far beyond the results of the spending cuts and can be traced back to four main factors. In this post, we would like to discuss to what extent his four main arguments also apply to the European scientific community. Continue reading
FS and FS+ are two distinct diseases, as suggested by twins
GEFS+ reloaded. The genetics of Febrile Seizures (FS) is one big mystery. Even though large families have been reported and multiple linkage studies have been performed, no single susceptibility gene for Febrile Seizures is known. This is somehow surprising, given that FS is by far the most common epilepsy syndrome. In contrast to common FS, genetic research has been very successful in families with Genetic Epilepsy with Febrile Seizures Plus (GEFS+), where Febrile Seizures Plus (FS+) are the most striking feature in families. Ever since the definition of the GEFS+ spectrum was established, the distinction from common FS has been a matter of debate. Now a twin study in Epilepsy Research suggests FS and FS+ might actually be two very distinct diseases with little genetic overlap. Continue reading
Familial Partial Epilepsy with Variable Foci and mutations in DEPDC5
A long story, a complicated phenotype. Massive parallel sequencing technologies were an innovation in neurogenetics and made the discovery of many genes underlying familial epilepsies possible. However, some epilepsy syndromes turned out to be more “stubborn” than others. Now, in a back-to-back submission in Nature Genetics, two groups report on the gene underlying Familial Partial Epilepsy with Variable Foci (FPEVF). And no, it’s not an ion channel this time. Continue reading
Axiomatic – identifying a novel epilepsy gene that was hidden right before your eyes
The Hague, winter of 1997. Last week challenged my most basic beliefs, which reminded me of “Axiomatic”, a collection of science fiction short stories by Greg Egan. While on holiday in the Netherlands in 1997, I had bought this book in the Den Haag Centraal bookstore, and subsequently lost it or gave it away. I only remembered the title three weeks ago, and ordered it online. The book arrived at the same time that news from Antwerp twisted my brain. In the signature story of “Axiomatic” with the same title, a man acquires a nano-robot based implant that allows him to change his innermost convictions (I told you that it’s science fiction, right?). He basically wants to have the courage to kill the man who murdered his wife. After carrying out his revenge and after the effect of the axiomatic implant has worn off, he starts craving for more, since he is missing the certainty in his life that the implant had given him. I needed to adjust my deeply held expectation on how to find de novo mutations after Tania, a PhD student in the Antwerp lab, had pulled out a de novo mutation in one of our trios that Denovogear had missed. This mutation turned out to be another hit in a gene that we had seen before. Continue reading
Pushing the button for the next exome sequencing round
Galvanize. Last week, the EuroEPINOMICS RES working groups made the final decisions for the selection of trios for exome sequencing at the Sanger Centre, funded jointly by the Sanger Programme on paroxysmal neurological disorders and the EuroEpinomics RES fund. We pushed the button for 102 patient-parent trios to be sequenced. And for some reason, I caught myself humming “Galvanize“, the 2005 big beat hymn by the Chemical Brothers. Continue reading
How to detect de novo mutations in exome data
Taking things apart. Looking for de novo variants using trio exome sequencing is a powerful technique to identify disease-related genes. After having introduced samtools during the last post, this will be post 2/3 in a series on how to perform an analysis of exome data for de novo variants. This time, I would like to take apart the methods that take us from Gigabyte BAM files to small tables with likely variants. So buckle up. Continue reading
The return of TBC1D24
First of its kind. In 2010, a virtually unknown gene became the first epilepsy gene to be discovered through massive parallel sequencing techniques. This gene, TBC1D24, was found in two recessive families with different types of epilepsy. Afterwards, it became silent around this gene with no further findings. Now, a recent paper reports on a third family with a mutation in this gene with a complex phenotype of epileptic encephalopathy and movement disorders. As the mutation is located in an alternative exon of this gene, this raises important issues on how we identify and interpret mutations. Continue reading
