KCNB1 encephalopathy – widening the phenotypic spectrum

KCNB1 encephalopathy. Pathogenic variants in KCNB1 were first reported three years ago in three unrelated patients with an early-onset epileptic encephalopathy. Since the initial report, individual patients have been reported with de novo KCNB1 variants, but a comprehensive overview of the KCNB1 encephalopathy clinical picture has been lacking. A recent publication by de Kovel and colleagues provides a comprehensive overview of the clinical features and genetic variants in 26 individuals with KCNB1 encephalopathy, including 16 previously unreported patients, providing novel insights into the phenotype. In this post we will unpack this publication, including what new information about KCNB1 it tells us. Continue reading

Navigating choppy waters: psychosocial implications of uncertainty

Psychosocial implications of uncertainty. As navigators of genetic testing, genetic counselors have seen it all – smooth seas, choppy waters and even the rare tsunami. Genetic testing sounds, well, so promising. Huge gene panels for epilepsy, whole exome sequencing – guaranteed to find an answer, right? Wrong. And let’s not even talk about secondary (incidental) findings, variants of uncertain significance and (gulp) non-paternity. While our technology has changed, navigating the choppy waters of psychosocial issues in genetic testing has not. Previous EpiGC posts to this blog have highlighted the challenges inherent to interpreting variants of uncertain significance. Now let’s talk about the psychosocial implications of dealing with uncertainty.

Continue reading

Genetic testing in early-onset epilepsies: approaching a new consensus?

Early-onset epilepsies. In recent years, we have discovered several causative genes for severe epilepsies beginning in the first year of life, including KCNQ2, SCN2A, and STXBP1. Several studies have reported a high yield of diagnostic genetic testing, including NGS panel approaches and whole exome sequencing, particularly in patients with seizure onset in the neonatal period where detection rates are often reported to be above 50%. Two recent studies add to the growing pile of evidence that genetic testing, and in particular NGS-based testing methods, are valuable in the diagnostic workup of children presenting with seizures early in life. Will these two studies help push us towards a new consensus regarding genetic testing in epilepsy?

Continue reading

SCN1A-related epileptic encephalopathy: Beyond Dravet syndrome

SCN1A phenotypes. Readers of Beyond the Ion Channel will know that we often post about SCN1A, one of the first discovered and most common genetic causes of epileptic encephalopathy. We more or less assume that we understand the phenotypes associated with pathogenic variants in SCN1A: most commonly Dravet syndrome, which is associated with de novo variants, and less commonly genetic epilepsy with febrile seizures plus (GEFS+), associated with inherited missense variants. However, a recent publication by Sadleir and colleagues suggests that the phenotypic spectrum of SCN1A-related disorders may be broader than we have previously appreciated. Are there SCN1A-related epileptic encephalopathies in addition to Dravet syndrome? Continue reading

Five things I learned at the FamilieSCN2a Annual Family and Professional Conference

FamilieSCN2A. On July 14th and 15th, Ingo and I had the pleasure of speaking at the FamilieSCN2a Annual Family and Professional Conference, which was hosted at the DuPont Children’s Hospital in Wilmington, Delaware. This meeting brings together families of children and young adults with SCN2A-related disorders and medical professionals and scientists working in the field, with the purpose of sharing information, learning from one another, and moving the field forward. This post won’t be a comprehensive recap of all that was discussed, since we heard from a broad range of professionals including therapists, electrophysiologists, epidemiologists, neurologists, and geneticists and it would be nearly impossible to sufficiently summarize everything. But I did want to share some of my impressions and thoughts. Here my five things I learned at the FamilieSCN2a Conference. Continue reading

Into the epilepsy phenome

Genome to phenome. Meaningful patterns in human diseases are often only revealed when looking at larger groups of patients. Over the last decade, we have figured out how to make genetics scalable to fit this need. High-throughput genetics can now be performed on an industrial scale with the possibility of assessing almost every base pair in the human genome in thousands of people. Phenotyping, however, has remained a non-scalable task, requiring repeated review, extraction, and interpretation of phenotypic data. In addition, there is no agreed-upon format for phenotypic data that parallels the standards we have in genetics. To overcome this problem, projects such as the Epilepsy Phenome/Genome Project (EPGP) have collected systematic, standardized phenotypic data upfront on every patient. In a recent study in Neurology that analyzed familial clustering of phenotypes within this dataset, we get a first view of what working with the epilepsy phenome may look like. We were asked to provide an editorial for this study where we emphasized that systematic phenotyping in large datasets can reveal phenotypic patterns that are beyond our understanding of disease genetics.  Basically, the phenome suggests patterns that are contradictory to what we think genes would do. Continue reading

DNM1 encephalopathy – a new disease of vesicle fission

Dynamin 1. Our recognition of DNM1 encephalopathy as a novel disease started out as a digital flicker. Deep inside some of the large-scale studies in epilepsy genetics, there were a few patients with de novo mutations in the gene coding for DNM1. However, amongst all the other likely and less likely candidates, it took a while for DNM1 to emerge as a true candidate. But even then, being a disease gene born out of large-scale studies with little information on clinical presentation and disease course, we had learned little about how patients with DNM1 encephalopathy actually present and how they develop over time. In our recent publication in Neurology, we describe the spectrum of DNM1 encephalopathy, including an unusual mutational landscape and the first genetic cause in a patient with FIRES. Continue reading

Three things I learned about focal epilepsies on the Faroe Islands

Focal to genetic. While there was little interest in the genetics of focal epilepsies only five years ago, the field has gained significant momentum since the discovery of DEPDC5 and the subsequent new appreciation of the mTOR pathway. This finding resulted in several gene discoveries and linked traditional genetic epilepsies with the emerging field of somatic mutations. In May 2017, the European epilepsy genetics community met on the Faroe Islands for the international conference on focal epilepsy. Here are the three things that I learned about focal epilepsies on the Faroe Islands. Continue reading

Absence of evidence – where are the recessive epilepsy genes?

E2. When we work up a new-onset epileptic encephalopathy in clinical practice, there is a discrepancy between what we know and what we do. While we know that we have an almost 30% chance to find a causative de novo mutation in any of the known epilepsy genes, we usually think about a possible underlying inherited metabolic disorder when we order our first round of tests. However, the full phenotypic spectrum is often unknown and the question remained how many of these inherited metabolic disorders are missed. In our recent publication of the E2 consortium, we looked for evidence of inherited genetic disorders in patients with epileptic encephalopathies. Follow us on our journey that led to a negative answer, but uncovered a complexity in finding inherited diseases that we did not anticipate. Continue reading

E2 – collaborations and lessons learnt

E2. The advent of next generation sequencing allowed unimagined scope for large scale genetic studies. It quickly became clear that whilst new technologies could be used to solve single families, major advances would only occur by collaboration. This led to the formation of a number of Consortia – in the United States EPGP leading onto Epi4K and in Europe EuroEPINOMICS and EpiRES etc as well as a number of smaller consortia. Even with these multicentre collaborations it was clear that “bigger was better”, and attempts were made to try and synergize efforts across continents.  Continue reading