Computational phenotypes. Clinical epilepsy research requires the capturing of complex information in a way that then can be subjected to statistical analysis. For the analysis on the phenotype level, new standards are emerging that are heavily informed by genetic studies. In fact, in addition to the known domain-specific classifications such as the ILAE classification for epilepsy, interdisciplinary action is often required to improve the classification of neurological syndromes for a larger analysis. During the upcoming EMBO Practical phenotyping course in Luxembourg, we will introduce trainees in the field to concepts like the Human Phenotype Ontology (HPO), a controlled vocabulary to characterize syndromes and one of pillars of research in complex syndromes such as epilepsy and how to address aspects not covered in HPO. The course will be held in Luxembourg from Oct 4 to Oct 10, 2018. There has already been a strong interest in this course, but we have a few spots left if you would like to register!
ClinGen Epilepsy Gene Curation Expert Panel. For the past year I have been a member of the ClinGen Epilepsy Gene Curation Expert Panel, which has been a rewarding professional experience. I have gotten to know several colleagues within the epilepsy and ClinGen communities, I’ve become familiar with resources for gene curation including MONDO and HPO, and I’ve dived deeply into the existing literature linking genes with a broad spectrum of epilepsies. But working with ClinGen has had another unexpected benefit – it has influenced my approach to writing scientific manuscripts. I have been able to apply this knowledge recently when writing a manuscript about a new causative gene for developmental and epileptic encephalopathies. In this post I would like to share five insider tips about what to include in your genetics manuscript so that it can receive full consideration from the ClinGen Epilepsy Expert Panel.
Trio exomes. The concept of neurodevelopmental disorders is an umbrella term including intellectual disability, developmental delay, and autism spectrum disorder. About one quarter of these patients have epilepsy, including epileptic encephalopathy, in which the epileptic activity itself contributes to developmental delay or regression. One major cause of these disorders are de novomutations, which are present in the child but not present in either of the parents. A recent publication in Nature Genetics looked for de novo variants in nearly 6,700 patients with neurodevelopmental disorders, nearly 2,000 of whom had epilepsy. This study is an order of magnitude larger than the largest previous study of this kind and represents an important effort in epilepsy genetics. Here is what we want to review their major findings. Continue reading
Baggersee. With an unprecedented heat wave hitting the northern hemisphere, I eventually found my annual vacation blog post. I wrote blog posts about our beach vacation in Marielyst, Denmark, or Rehoboth Beach, Delaware. However, this year, it took me the better part of two weeks to realize that I had this year’s beach right beneath my feet – the small artificial beach of the Rossenray Lake, a small lake in my home town in Germany where we spent our summer vacation. And here are the three things the beach (and the lake) told me about science in 2018. Continue reading
Somatic mosaicism in focal epilepsy. Recent findings highlighted the role of somatic parental mosaicism in epileptic encephalopathies. However, somatic mosaicism has also emerged over the last few years as a prominent mechanism in the pathogenesis of lesional focal epilepsies, including focal cortical dysplasia (FCD) type 2 and hemimegalencephaly. Previous studies have identified the role of mosaicism of genes such as MTOR, TSC1/TSC2, and genes encoding components of the PI3K/AKT pathway in patients with epilepsy secondary to brain malformations. A recent study in Annals of Neurology has identified a new unrelated genetic cause of refractory non-lesional focal epilepsy, which leads us to wonder what role mosaicism may be playing in focal epilepsies without obvious findings on MRI.
Epilepsy gene panel. Testing for genetic causes in human epilepsy is typically performed using gene panels. In contrast to our research-based exome studies in an academic setting, much of the gene panel testing is performed through commercial laboratories and much of the existing data is usually inaccessible to the scientific community. In a recent publication in Epilepsia, a large US-based diagnostic laboratory reports on some of their existing data on epilepsy gene panels by reporting the results of more than 8500 epilepsy gene panels – a cohort size that is more than five times larger than any prior exome or gene panel study in the epilepsy field. I was asked to write an editorial on this publication, and I also wanted summarize on our blog three key messages that you can take away from this study. Continue reading
Genetic literacy. Sometimes important milestones don’t feel like much when you eventually reach them. Last Thursday, I woke up sleep-deprived after working on a grant all night and found an NCBI update in my mailbox. Primer Part 2 of the genetic literacy series of ILAE Genetics Commission was now published in Epilepsia and available on PubMed. Finally, both the introductory primers of the genetic literacy series are out – Part 1 dealing with the building blocks including general concepts of epilepsy genetics and epidemiology and now Part 2 about the paradigm shifts that were introduced with the advent of massive parallel sequencing. Both publications were revised and re-written over and over again to fit the overall didactic mission of the literacy series, an effort that takes approximately 10x as long as writing a typical review. But finally, as of May 10, 2018, both Primers are now in their final shape, published and open access to the international epilepsy community. And here is just a quick overview of what this paradigm shift is really about. Continue reading
Conventional wisdom. Trio whole exome sequencing has been successful over the last five years in identifying underlying genetic etiologies in nearly 50% of patients with epileptic encephalopathies, which is largely owing to the genetic architecture of these conditions. The vast majority of these genetic epilepsies are caused by apparent de novo variants that are present in the patient but not in the mother or father. The conventional wisdom is that the recurrence risk in future pregnancies for parents of an affected child is low to non-existent and traditionally we have quoted a ~1% recurrence risk for future pregnancies. However, a new study published in the New England Journal of Medicine turns this conventional wisdom on its head, identifying detectable somatic mosaicism in approximately 10% of parents tested, which has implications for how we counsel families of children with epileptic encephalopathies – and potentially other genetic conditions due to de novo variants as well. Continue reading
Unravelling the BAFME mystery. The mystery surrounding Benign Adult Familial Myoclonic Epilepsy (BAFME) – also known as Familial Adult Myoclonic Epilepsy (FAME) or Familial Cortical Myoclonic Tremor and Epilepsy (FCMTE) – has persisted for years. BAFME is an autosomal dominant neurological disorder characterized by adult onset of myoclonic/cortical tremor and infrequent seizures. The clinical course is typically considered to be benign. Linkage studies have shown linkage to several regions including 8q24, 2p11.1-q12.2, 3q26.32-q28, and 5p15. A recent publication identified a variant in CTNND2 segregating with disease in a Dutch family with BAFME3, although it remains to be determined how broadly applicable CTNND2 variants are in other individuals with BAFME. Now in an elegant set of experiments by Ishiura and colleagues, a significant proportion of BAFME appears to be solved and is due to expansions of pentanucleotide intronic sequences in SAMD12.
MPP. Mitochondria are indispensable for cellular energy production and require constant protein import, as most mitochondrial genes are encoded in the nucleus. In order for proper targeting, mitochondrial proteins have a specific presequence, which is removed once a protein has found its way into the mitochondria. This function is accomplished by the mitochondrial processing peptidase MPP, which is encoded by the PMPCA and PMPCB genes. In a recent publication in the American Journal of Human Genetics, we identified PMPCB as a novel gene for a complex neurodegenerative condition in childhood and discovered a new disease mechanism for neurological disorders. However, epileptic encephalopathy that initially led to the inclusion of our initial RES study was only one extreme of an unusual disease spectrum. Continue reading