Launch. This week, the Epilepsy Genetics Initiative (EGI) was launched. EGI was founded by Citizens United for Research in Epilepsy (CURE) and represents a large database for diagnostic and research exomes that will guarantee regular re-analysis of exome data, which is particularly relevant for the large number of exomes that we think are negative. Here is a brief blog post why all exomes should eventually find their way into EGI. Continue reading
25,000 genomes. The epilepsy community is currently preparing for the largest sequencing project in the epilepsies so far, responding to a call by the National Human Genome Research Institute (NHGRI). If funded, the Epi25 project will allow us to begin sequencing 25,000 individuals with epilepsy, helping us to achieve the next, necessary level for gene discovery in human epilepsies. Here are some of the reasons why we need Epi25 and why you should be part of it. Continue reading
Peds vs. adult. Sometimes it makes a fundamental difference in diagnosis whether a patient is seen in a pediatric setting or by an adult specialist later in life. Here is the most recent example from our consortium, which was just published in Human Molecular Genetics: what initially looked like recessive inheritance with intellectual disability and a peculiar fever-associated epilepsy syndrome eventually turned out to be the second reported family of the novel spastic paraplegia gene AP4S1. This raises the question of how much we are missing if we are looking at the wrong point in time. Let’s have a look at how genetics can help us see an overlap of diseases where we usually don’t have a chance to. Continue reading
Exome rounds. How will next-generation sequencing technologies impact on patient care in the future? What role will genetic analyses play in routine health care? Sometimes, the possible role of genetic information is compared to the role of MRI imaging, including the general expertise that is required of clinicians who apply these technologies but are not necessarily dedicated experts in the field. Here are three interesting parallels between exomes and MRI – and three examples how the impact of these technologies differs drastically. Continue reading
Exome failures. Trio exome sequencing has the huge potential to discover the genetic basis of neurodevelopmental disorders. However, the results are negative for the majority of patients. In a recent study published in Nature, genome sequencing was applied to exome-negative patients with intellectual disability, identifying mutations in coding regions that were previously missed. But are the authors correct in stating that they can explain more than 60% of cases in an unselected cohort? Continue reading
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.
Climate change. In the era of exome and genome sequencing, it might be worthwhile revisiting the merit of family studies in epilepsy research. Seizure disorders are known to have a highly diverse genetic architecture. When singleton studies identify a single, unique gene finding, this discovery usually does not provide much information about the potential causal role of the variant given the high degree of genomic noise. In contrast, family studies are usually considered more robust, as segregation of variants can be traced. Here is the inconvenient truth: unless the family is very large, segregation of possibly monogenic variants adds little information given the vast amount of variants present in our genomes. Continue reading
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
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
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