Outcomes and hidden subgroups in WDR45-related disorders

BPAN. WDR45-related disorders are one of the most common X-linked neurodevelopmental disorders. While initially conceptualized within the framework of rare conditions with neurodegeneration with brain iron accumulation, WDR45-related disorders challenge the traditional concept of neurodegenerative conditions. Most individuals are diagnosed in childhood with neurodevelopmental features. However, the full spectrum of the pediatric presentation of WDR45-disorders has not been fully delineated yet. In a recent publication, we delineate the pediatric presentation of WDR45-disorders. We find that typical outcome measures often fail to capture the full range of features in WDR45-related disorders and that there might be two distinct previously not appreciated subgroups. Continue reading

Phenotypic atomism – understanding outcomes by rethinking clinical information

Natural History. Over the last few years, there has been a renewed interest in outcomes and natural history studies in genetic epilepsies. If one of the main goals of epilepsy genetics is to improve the lives of individuals with epilepsy by identifying and targeting underlying genetic etiologies, it is critically important to have a clear idea of how we define and measure the symptoms and outcomes that characterize each disorder over a lifetime. However, our detection of underlying genomic alterations far outpaces what we know about clinical features in most conditions – outcomes such as seizure remission or presence of intellectual disability are not easily accessible for large groups of individuals with rare diseases. In this blog post, I try to address the phenotypic bottleneck from a slightly different angle, focusing on how we think about phenotypes in the first place. Continue reading

Rewriting the story of neurodevelopmental genes through CNVs in one million people

Copy numbers. When we think about genetic causes of neurodevelopmental disorders and the epilepsies, we typically discuss single genes and de novo variants. Over the last few years, exome and genome data of hundreds of thousands of people have been analyzed, creating large-scale resources to understand genetic variation in health and disease. However, there has been one resource that has always been larger by at least one order of a magnitude – information on copy number variation derived from SNP arrays and array CHG. Now, a recent publication pulls all the existing information together and performs a meta-analysis of rare copy-number variants in nearly one million people. Here is what this study tells us about neurodevelopmental genes and how we can use mismatches between CNV and exome data to answer old questions and find novel genes. Continue reading

Cosmic Spring, ATP1A3, and the dawn of the exome era

The exome decade. Last week, I accidentally looked back at our past blog posts. Exactly 10 years ago, we wrote about the discovery of ATP1A3 as the cause of Alternating Hemiplegia of Childhood (AHC). Quite a lot has happened since then in epilepsy genetics, including the discovery of at least twenty additional genes, initial clinical trials, and large-scale studies such as our Epi25 initiative. However, when seeing our 2012 blog posts, my immediate thoughts were not about achievement or progress – quite contrarily, I had the strange feeling that not much had changed in the last decade. I was reminded of a science fiction short story by Ken Liu – Cosmic Spring. Continue reading

Untying the Gordian knot – the return of Reelin

RELN. Amongst the various genes implicated in neurodevelopmental disorders, Reelin (RELN) has always been one of the more controversial genes. While bi-allelic variants have been implicated in lissencephaly with cerebellar hypoplasia, the role of autosomal dominant variants has been controversial and is currently considered disputed. Reelin is a relatively large gene – accordingly, missense variants are frequent. However, a recent study suggests that the picture might be more complicated and that both monoallelic and bi-allelic variant in Reelin may contribute to neurodevelopmental disorders. Here are my thoughts. Continue reading

A wrinkle in the polygenic risk story

PRS. While monogenic epilepsies are the main genetic etiologies diagnosed in clinical practice, the majority of the genetic epilepsies is not explained by single, strong genes. In contrast, on a population level, the main genetic risk for epilepsy is explained by common genetic variants. While these variants had been largely inaccessible in the past, recent studies have been successful in identifying these variants and understanding the joint risk for epilepsy that are conferred by multiple genetic factors. When assigned to individuals, this joint risk is typically measured as polygenic risk scores. In a recent study, we demonstrate that this finding extends to familial epilepsies, which are highly enriched for extreme polygenic scores. However, in the very moment that I was trying to type the first lines of this blog post, a similar study in schizophrenia appeared online, showing exactly the opposite. Here are some thoughts on why polygenic risk is not as straightforward as you would expect. Continue reading

Precision medicine is instructive when it fails

KCNT1. This is my third blog post on our precision medicine review by Knowles and collaborators. In this post, I wanted to review the experience with precision medicine in the epilepsy community since the initial precision medicine road map that we published in 2015.  Here is a quick summary of why the community’s experience with quinidine was an important lesson for the future. No, it did not fail, it simply revealed a weakness in the way we introduce repurposed medications into clinical practice and how we think about them. Continue reading

DDX3X, WDR45 and the ongoing mystery of X-linked disorders

X-linked. Almost a decade ago, the former EuroEPINOMICS team was asked to perform a difficult task. We reviewed inherited variants in X-linked genes, trying to understand whether inherited variants are causative of neurodevelopmental disorders for one of our research studies. In most cases, we decided that we did not have enough evidence. How could we tell whether variants in genes such as HUWE1 or CNKSR2 that were transmitted from unaffected females to affected sons were disease-causing or not? I remembered my frustration when I came across a publication on the contribution of X-linked variants to neurodevelopmental disorders that was published last year. Continue reading

How SCN1A comes to its own rescue

Modifier genes. When I compiled the most important updates on SCN1A genetics a few weeks ago, I forgot one of the most unusual studies that makes you pause and think. To provide some background: ever since the initial discovery of familial epilepsy syndromes such as Genetic Epilepsy with Febrile Seizures Plus (GEFS+), the intrafamilial range of presentations has been a big mystery. Within single families, we typically observe a very broad spectrum of phenotypes. Furthermore, in some families, the range of phenotypes is extreme – the same SCN1A variant may cause Dravet Syndrome in one individual, while other individuals are unaffected. In a recent study, we stumbled upon an unusual cause for this variability: a second SCN1A variant that neutralizes the pathogenic effect of the familial variant. Here is a summary of this unusual story. Continue reading

Understanding development and seizures in STXBP1 disorders

STX. I have to admit that the main gene that our team is working on has received relatively little attention on our blog, even as several manuscripts on STXBP1 have recently been published that add to our understanding of STXBP1-related disorders. I described STXBP1 at the Simons Foundation’s INSYNC-AS meeting as one of the genes with the “fastest growing knowledge,” now following close behind recognized neurodevelopmental disorders including Rett and Angelman Syndrome. In this post, I would like to feature one of our recent publications in Neurology Genetics that assessed the developmental trajectory of 48 individuals with STXBP1-related disorders. In particular, I would like to zero in on the most important result of this study, which expands on one of the controversies in the STX field. Continue reading