This was epilepsy genetics in 2021 – five things to remember

Looking back. Admittedly, I have not written an end-of-the-year review for a quite some time. However, there were a few notable moments in epilepsy genetics in 2021 that I think were worth remembering. The second year of the COVID-19 pandemic started out as a year of recovery and readjustment, only to run into unanticipated supply chain issues and novel COVID variants hanging over our transition into 2022. The scientific community was affected by these developments in different ways that made progress of science somewhat unpredictable and uneven. 2021 was the year when the phrase “unprecedented times” became stale and overused. Here are five things to remember from 2021, which will be remembered as part of a transitional phase in epilepsy genetics. Continue reading

This was AES 2021 – five takeaways from Chicago

Pandemic. This year’s Annual Meeting of the American Epilepsy Society (AES) was the 75th meeting, but it was a meeting like no other. #AES2021 was the first in-person meeting for the international epilepsy community with many international participants unable to join due to local restrictions and the US-based audience split between participating in-person and joining remotely. However, despite the unusual format, this year’s meeting was bustling and full of excellent science. Here are my five takeaways from AES 2021. Continue reading

STXBP1-related disorders: deciphering the phenotypic code

STX. Neurodevelopmental disorders due to disease-causing variants in STXBP1 are amongst the most common genetic epilepsies with an estimated incidence of 1:30,000. However, despite representing a well-known cause of developmental and epileptic encephalopathies in the first year of life, relatively little has been known about the overall genetic landscape and no genotype-phenotype correlations have been established. In our recent publication including almost 20,000 phenotypic annotations in 534 individuals with STXBP1-related disorders, we dive deep into the clinical spectrum, examine longitudinal phenotypes, and make first attempts at assessing medication efficacy based on objective information deposited in the Electronic Medical Records (EMR), including information from the almost 100 “STXers” seen at our center in the last four years. Continue reading

Introducing the revised Human Phenotype Ontology (HPO) – a new language for Big Data in the epilepsies

Classification. Our classification of the epilepsies periodically undergoes revision to align the way we think about the epilepsies with scientific progress in the field. While it is intuitive that relatively novel frameworks such as the 2017 International League Against Epilepsy (ILAE) Operational Classification of Seizure Types capture the current spirit of the field more accurately than prior classifications, one relatively simple question is not easily answered: how much more accurate? How we get to such an answer requires us to take a step back and think about how the value of clinical information can be measured and compared. In our recent publication, we describe the revision of the Human Phenotype Ontology (HPO) according to the most recent ILAE classifications and other respected definitions in current use. This gives the answer to the prior question: 40% (which is a lot). Continue reading

SCN2A – a neurodevelopmental disorder digitized through 10,860 phenotypic annotations

HPO. SCN2A-related disorders represent one of the most common causes of neurodevelopmental disorders and developmental and epileptic encephalopathies (DEE). However, while a genetic diagnosis is easily made through high-throughput genetic testing, SCN2A-related disorders have such a broad phenotypic range that understanding the full scale of the clinical features has been traditionally difficult. In our recent study, we used a harmonized framework for phenotypes based on the Human Phenotype Ontology (HPO) to systematically curate phenotypic annotations in all individuals reported in the literature and followed at our center, a total of 413 unrelated individuals. Mapping phenotypic data onto 10,860 terms with 562 unique concepts and applying some of the computational tools we have developed over the last three years, we were able to delineate the phenotypic range in unprecedented detail. SCN2A is now the first DEE with all available data systematically curated and harmonized in a computable format, allowing for entirely novel insights. Continue reading

Make data speak in rare childhood epilepsies

Capturing data. While genetic analysis can be performed and investigated on an industrial scale in thousands of individuals in parallel, the analysis of clinical data is frequently still the domain of manual data curation. Clinical data is typically collected in a non-standardized way, which makes it difficult for information generated in a clinical context to be used in a systematic data analysis as can be performed with genomic data. However, the tide is turning, and we are slowly coming around to the idea that clinical data also requires the same degree of standardization in order to be used at scale. For none of the epilepsies is such standardization more important than for the rare epilepsies, which include many of the genetic epilepsies. Our lab has been working on frameworks and methods to allow for this kind of analysis in genetic epilepsies. Here is a brief summary of what it actually means to “make data speak”, which has become the mission statement of our lab. Continue reading

The spectrum of de novo variants in 30,000 individuals with neurodevelopmental disorders

NDD. Trio-exome sequencing is the gold standard to identify the underlying genetic basis in individuals with neurodevelopmental disorders. De novo variants account for the vast majority of causative genetic findings once a diagnosis is made, but the overall genetic landscape is very heterogeneous, with few genes explaining more than 1% of the genetic morbidity. As the largest study of its kind to date, a recent publication in Nature assessed the spectrum of de novo variants in neurodevelopmental disorders in more than 31,000 individuals. The authors identify more than 250 disease-associated genes, highlight 28 novel genetic etiologies, and highlight signals in their data that hint at more than 1,000 disease-associated genes yet to be discovered. In this blog post, I have summarized the five take-home messages from this large study. Continue reading

OMIM to retire EIEE classification – an important step to overhaul terminology for genetic epilepsies

EIEE. Online Mendelian Inheritance in Man (OMIM) is the undisputed main resource for information regarding genes and disease. It is the resource that the majority of clinicians and researchers in the field turn to in order to get information about established or novel genetic etiologies in genetic epilepsies and neurodevelopmental disorders. However, historically, OMIM had decided to enumerate many of the genes for developmental and epileptic encephalopathies within a phenotypic series called Early Infantile Epileptic Encephalopathies (EIEE). The field has advanced, and we now understand that most genetic etiologies have a broad phenotypic range and can cause a wide range of epilepsy phenotypes. Accordingly, in collaboration and consultation with our ClinGen epilepsy clinical domain working group, OMIM will retire the EIEE classification and refer to them as developmental and epileptic encephalopathies (DEE). Dravet Syndrome, formerly EIEE6 will now become DEE6, which is the secondary annotation to the actual term “Dravet Syndrome”. For some, this might be a small change in semantics. However, as a clinician trying to make sure that the uniqueness and distinctiveness of childhood epilepsies in the era of large-scale data analysis is appreciated, this small step is likely to be highly influential in the future. Here is some background on how the EIEEs finally became DEEs. Continue reading

DNA methylation, somatic mutations, and polymicrogyria

MCDs. Malformation of cortical developments are a frequent cause of intractable epilepsies and, if appropriate, surgical resection may be warranted. Malformations represent a wide range of cortical lesions resulting from derangements of normal intrauterine developmental processes affecting the formation of the cortical mantle. Polymicrogyria (PMG) is one of the most common malformations of cortical development. However, while somatic mutations affecting the mTOR pathway are a known cause of certain subtypes of MCD, the polymicrogyrias have remained elusive. The underlying cause remains unknown in more than 80% of cases and, if identified, may be due to a wide range of underlying genetic causes. In a recent publication, mosaic trisomy 1q was identified as a novel and relatively frequent cause of polymicrogyria, emphasizing the role of somatic mutation detection in malformation of cortical development. Continue reading

Understanding patient advocacy – the Rare Epilepsy Landscape Analysis (RELA)

The Rares. The increasing number of genetic diagnoses in rare epilepsies has resulted in the formation of a large number of non-profit organizations and support groups over the last decade.  These support organizations for rare epilepsies (“Rares”) have already had an important impact on the epilepsy genetics field. However, the overall impact, direction, and needs of the Rares have never been assessed systematically.  In a recent editorial, Ilene Penn Miller summarized the findings of the Rare Epilepsy Landscape Analysis (RELA), which surveyed 44 advocacy and support organizations for rare epilepsies. Continue reading