Exome sequencing in epileptic encephalopathies – a classification of de novo mutations

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

Live at Covent Garden – the ERC Starting Grant Interviews

On stage. I just got back from Brussels where I had to defend my ERC Starting Grant in front of the Neuroscience Panel. The European Research Counsil (ERC) Starting Grants are prestigious excellence grants and I was lucky enough to be invited for the famous second round. This second round requires the applicants to go to Brussels in order to give a 10-15 min presentation and defend the application on the 24th floor of the Covent Garden building. It provides a wonderful view of the city, but nobody really bothered taking this in. Let’s use the opportunity to quickly discuss grants, funding and the future of epilepsy genetics. Continue reading

Sturge-Weber syndrome explained – somatic mutations in GNAQ

Phakomatoses. There are a group of disorders that affect both the skin and the central nervous system. These disorders, called neurocutaneous disorders or phakomatoses, may result in epilepsy or intellectual disability, depending on the extent to which the brain is affected. While a genetic basis for some neurocutaneous disorders including Tuberous Sclerosis Complex (TSC) and neurofibromatosis is known, the etiology of other neurocutaneous diseases remains unknown. Now, a recent paper in the New England Journal of Medicine reports on the genetic alterations underlying one of the most common neurocutaneous disorders, Sturge-Weber syndrome. 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

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

STRADA mutations, mTOR activation and personalized medicine using rapamycin

Rapamycin. The mTOR pathway, known through its role in Tuberous Sclerosis Complex (TSC), becomes increasingly important in epilepsy. A wide range of epilepsies caused by brain malformations are due to mutations in genes involved in this pathway, and several neurodevelopmental disorders associated with macrocephaly, intellectual disability and epilepsy are known, where components of this pathway are altered due to germline mutations. For one of these disorders named PMSE (polyhydramnios, megalencephaly and symptomatic epilepsy), a recent paper in Science Translational Medicine reports the effects of treatment with rapamycin, an mTOR inhibitor. The results demonstrate that personalized medicine might in part be promising, asexisting drugs can be used in rare genetic diseases. Continue reading