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

The SCN1A rs6732655 enigma – a reply

rs6732655. I acknowledge that the title of this blog post looks like my keyboard is broken, but please bear with me. Last month, I blogged about a recent genome-wide association by the BioBank Japan (BBJ), discussing the evidence for a Single Nucleotide Polymorphism (SNP) in the vicinity of the SCN1A gene (rs6732655). In a prior study, the SNP in question was initially found to be associated with epilepsy and I discussed the fact that this SNP, albeit not significant by itself, was also seen at a higher frequency in cases than in controls in the epilepsy cohort of the BBJ study. I received some comments regarding this post and it was pointed out that my reasoning was incorrect given that rs6732655 was not nominally significant in the BBJ study. Therefore, this study was not a replication study in itself. Let me retrace my steps and revisit where my hunch came from to write the initial blog post. Continue reading

Entering the phenotype era – HPO-based similarity, big data, and the genetic epilepsies

Semantic similarity. The phenotype era in the epilepsies has now officially started. While it is possible for us to generate and analyze genetic data in the epilepsies at scale, phenotyping typically remains a manual, non-scalable task. This contrast has resulted in a significant imbalance where it is often easier to obtain genomic data than clinical data. However, it is often not the lack of clinical data that causes this problem, but our ability to handle it. Clinical data is often unstructured, incomplete and multi-dimensional, resulting in difficulties when trying to meaningfully analyze this information. Today, our publication on analyzing more than 31,000 phenotypic terms in 846 patient-parent trios with developmental and epileptic encephalopathies (DEE) appeared online. We developed a range of new concepts and techniques to analyze phenotypic information at scale, identified previously unknown patterns, and were bold enough to challenge the prevailing paradigms on how statistical evidence for disease causation is generated. Continue reading

Copy Number Variations in the epilepsies – a 2020 update

CNV. There are different forms of genetic variation and historically, our ability to query the entire exome or genome is a relatively recent development. However, the first type of genetic variation that could be assessed in the epilepsies in large cohorts were copy number variations (CNV), small gains or losses of chromosomal materials. In a recent study, the entire Epi25 cohort was analyzed for CNVs, giving a long-needed update on the role of the structural genomic variations in various forms of epilepsies and highlighting that the overall landscape of CNVs in the epilepsies is well understood and delineated. With up to 3% of individuals with epilepsies carrying some of the recurrent CNVs, this type of genomic variation remains a rare, but important source of genetic morbidity in the epilepsies. Continue reading

The natural history of genetic epilepsies as told by 3,200 years of electronic medical records

EMR. When we consider the natural history of rare diseases like the genetic epilepsies, we typically think about a lack of longitudinal data that contrasts with the abundant genetic information that is available nowadays – the so-called phenotyping gap. We typically suggest that we need to obtain this information in future prospective studies to better understand long-term outcome, response to medications, and potential early warning signs for an adverse disease course. However, a vast amount of clinical data is collected on an ongoing basis through electronic medical records (EMR) as a byproduct of regular patient care. In a recent study, our group built tools to mine the electronic medical records to assess the disease history of 658 individuals with known or presumed epilepsies using clinical information collected at more than 62,000 patients encounters across more than 3,200 patient years. Here is a brief summary of our first study on EMR genomics, an untapped resource that has the potential to improve our understanding of the genetic epilepsies. Continue reading

GNAO1 and 13K genomes – rare disease sequencing on a national level

WGS. Whole-genome sequencing is increasingly used to understand the cause of rare diseases in a research and diagnostic context. However, while the usefulness of this technology has been shown in smaller studies, it remains unclear whether strategies to understand the cause of rare disorders through whole genome sequencing can be performed on a national level. A recent study in Nature reported the first results from a national sequencing campaign for rare disorders in the UK, including the analysis of more than 13,000 genomes. In this blog post, I would like to focus on the neurogenetics component of this enormous study, which identified disease-causing variants in GNAO1 as the most common cause within the study’s subgroup of neurological and developmental disorders. Continue reading

Common genetic risk factors for epilepsy in the Japanese population

GWAS. While our blog mainly deals with monogenic epilepsies, assessing common genetic risk factors through genome-wide association studies has been an established way of understanding potential genetic contributors to both common and rare disorders. More recently, polygenic risk scores have entered the stage, composite measures of many common variants which explain a significant proportion of the overall population risk for epilepsy. However, a major limitation of many genome-wide association studies has been the focus on populations of European ancestry. So far, very few studies have examined common genetic risk factors in the epilepsies in non-European populations. In a recent publication examining results from the BioBank Japan Project, 42 disorders were examined in more than 200,000 individuals, including the epilepsies. While no single epilepsy variant stood out, the study provides an interesting confirmation of a previously known common risk factors for the epilepsies. Continue reading