A large-scale analysis of KCNQ2 variants – overcoming the functional bottleneck

KCNQ2. I have to admit we have not written about KCNQ2 for a while, which does not do justice to the role of KCNQ2 in human epilepsies. KCNQ2-related epilepsies represent some of the most common genetic epilepsies and almost exclusively present with neonatal seizures. Historically, KCNQ2 was identified in families with self-limiting neonatal seizures. Subsequently, disease-causing variants were also identified in neonatal developmental and epileptic encephalopathies (DEEs). While self-limiting epilepsies were attributed to protein-truncating variants, KCNQ2-related DEEs are attributed to dominant-negative variants. However, as in many other DEEs, this conceptual black-and-white distinction is somewhat oversimplified, and the genotype-phenotype correlation in KCNQ2-related disorders is more complex. In a recent study, we assessed a total of 81 KCNQ2 variants’ functional effects in parallel, leading to some unexpected results about the function of disease-related KCNQ2 variants. Here is what this first large-scale electrophysiological analysis of an epilepsy-related ion channel told us. Continue reading

Epi25 – redefining epilepsy genetics through exomes of 17,000 individuals

The Epi25 study. On August 1, the Epi25 study was published in the American Journal of Human Genetics. Epi25 is the major, international effort to understand the genetics of common and rare epilepsies through exome sequencing, and our current study now presents the first results on what we can see if we look at the genetics of the epilepsies in thousands of individuals, including more than 9,000 persons with epilepsy and 8,000 controls. The Epi25 study finds that individuals with epilepsy carry more ultra-rare, deleterious variants than controls, especially in known or presumed candidate genes. This is a significant finding that tells us about the inner genetic architecture of the epilepsies beyond the role of monogenic causes. However, as with many previous studies at this scale, the first publication merely scratches the surface and provides an enormous amount of data for further studies. Here is a brief summary of the Epi25 study and some of the most prominent genes in the epilepsies that were completely unknown previously. Continue reading

HCN1 enters the GEFS+ sphere

HCN1 update. Hyperpolarization-activated cation channels (HCN) are involved in neuronal pacemaker activity and regulate neuronal excitability through hyperpolarization-activated Icurrent. In 2014 de novo missense variants in HCN1 were identified in five unrelated individuals with a Dravet Syndrome-like developmental and epileptic encephalopathy (DEE). However, in the intervening four years relatively little additional evidence has emerged regarding the role of HCN1 in epilepsy. Now, a recent publication in Brain identifies additional individuals with HCN1-related epilepsies and significantly expands the clinical spectrum beyond Dravet-like DEE. Continue reading

CACNA1E encephalopathy: a new calcium channel disease

The calcium connection. Pathogenic variants in genes encoding voltage-gated ion channels have long been known to cause neurological disorders in people. Dravet syndrome, caused by pathogenic variants in the neuronal sodium channel-encoding gene SCN1A, is one of the most common channelopathies. Although sodium and potassium channels play an established role in childhood-onset epilepsies, the role of voltage-gated calcium channels has been less clear. We have known for over a decade that disease-causing variants in CACNA1A cause a spectrum of neurological disorders, including developmental and epileptic encephalopathies. But evidence of a role for other neuronal calcium channels in epilepsy has been sparse until now. Our publication in the American Journal of Human Genetics now explores the phenotype and functional consequences of de novo variants in CACNA1E, representing a new and unexpectedly frequent disease entity.
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The IQSEC2 mystery – exploring the phenotype of an X-linked disease in males and females

The X-factor. Interpreting variants in X chromosome genes in a clinical context is an ongoing diagnostic challenge, regardless of whether the variant is identified in a male or female patient. The majority of X-linked conditions affect hemizygous male individuals, with heterozygous carrier girls and women largely unaffected or much less severely affected. PCDH19-Epilepsy is, of course, a notable rule breaker in this regard. However, we are learning that other X-linked conditions don’t play by the traditional rules either, and affected heterozygous females are being described for some other X-linked conditions. In some cases, including SMC1A– and NEXMIF– (formerly called KIAA2022) related disorders, the phenotypes in males versus females are more or less distinct. However, in other X-linked conditions, including IQSEC2-encephalopathy, both affected males and females share a continuum of similar features. A recent publication in Genetics in Medicine explores and expands the spectrum of IQSEC2-encephalopathy and delves into what is similar – and what is distinct – in affected male and female patients. Continue reading

The first Online Symposium: Rare Genetic Variants Associated with Neurodevelopmental Disorders

Online. Last week, we held the first online symposium on “Rare Genetic Variants Associated with Neurodevelopmental Disorders”. The meeting covered seven topics which included different genomic approaches used to unravel the genetic architecture of neurodevelopmental disorders and cognitive traits. In total, 117 participants joined the meeting with a peak of 72 participants listening to a presenter. Continue reading

Here is why CADD has become the preferred variant annotation tool

Variant annotation. In both clinical practice and within existing research projects, we’re often faced with the issue of telling whether a given variant is benign or whether it is pathogenic. In silico prediction tools are designed to help this decision making process. However, there are so many of them and it is often hard to assess which tool works best. In a 2014 publication in Nature Genetics, the CADD score was introduced as comprehensive tool that aims to take the results of many known prediction tools into account. Follow me on a journey that takes us on hyperplanes, support vector machines and every possible variant in the human genome. Continue reading

Mysteries of a neuronal pathfinder – this is what you should know about PCDH19 in 2015

Protocadherin. There are some genes that we have mentioned less frequently on our blog than we should have. PCDH19 and CDKL5 are two examples of this. With this post, we try to catch up by reviewing some of the new findings related to PCDH19 Female Epilepsy including the role of neurosteroids, anti-NMDA receptor antibodies, stiripentol and the mechanism behind this epilepsy. Continue reading

Publications of the week: CDKL5, KIF1A, and familial cortical tremor

Issue 7/2015. I am realizing that we are a little behind with our weekly paper review and I hope that we can use the month of July to catch up. Our publications of the week include functional studies on CDKL5 targets that may suggest future therapy development, the recessive/de novo paradox of KIF1A and an attempt to understand the genetics of familial cortical tremor. Continue reading