The second ILAE GWAS or why 30% of genetic generalized epilepsy is explained

Genome-wide association. While most of the neurogenetics community was focused on exome sequencing and the discovery of novel monogenic forms of epilepsy in the last few years, something quite remarkable had happened in the background. Common variants and genome-wide association studies have made a remarkable comeback. The ILAE Consortium for Complex Epilepsy had slowly worked on increasing sample sizes over time, and the second analysis of common variants in common epilepsies was published in late 2018. Sample sizes have almost doubled since the first study in 2014, and as a result, the number of genome-wide significant loci has tripled. However, the most intriguing finding was something that completely caught me by surprise – more than 30% of the heritability of the genetic generalized epilepsies is explained through common variants, approaching the numbers we see in epileptic encephalopathies explained by monogenic causes. This is one more reason to discuss the recent ILAE GWAS in more detail. 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

Ultra-rare genetic variants in familial epilepsies

The final frontier. The last five years have seen enormous progress in understanding the genetic basis of sporadic severe, treatment-resistant epilepsies due to de novo mutations. However, there has been much less progress in understanding the basis of familial epilepsy, which has historically been the major focus of epilepsy genetics. Particularly small families with mild epilepsies are challenging to solve, with the exception of rare families with pathogenic variants in known epilepsy genes. Exome-first approaches in familial epilepsy are particularly challenging given the sheer amount of variants segregating in small families by chance. In a recent publication by the Epi4K Consortium, a novel approach is presented to identify the genetic basis of familial epilepsies, overcoming the limited power of small families by analyzing rare variants in probands in a case/control study design. Here are some fascinating insights from this study. Continue reading

GABRB3, 15q dups, and CNVs from exomes

GABAergic. Let’s start out with a provocative statement. There is a single gene that may explain more cases of Lennox-Gastaut Syndrome (LGS) and Infantile Spasms (IS) than you would expect, rivalling SCN1A for the most common gene found in this group of patients. It’s a gene that you are probably aware of but that you may think to be a very rare finding. In a recent publication in Annals of Neurology, the Epi4K consortium published their recent analysis of copy number variations that were derived from exome data. Combining de novo mutations and copy number variations points to GABRB3 as a major player in LGS and IS, explaining probably more than 2% of patients. Let’s find out about the twilight zone, strategies to obtain structural variants from exomes, and the re-emergence of the 15q duplication syndrome. Continue reading

The microdeletion landscape of Genetic Generalized Epilepsy

CNV. Structural genomic variations or Copy Number Variations (CNVs) significantly contribute to the genetic architecture of many neurodevelopmental disorders. However, given the enormous variation in the human genome in healthy individuals, the precise contribution of CNVs remains poorly understood. In a recent publication in PLOS Genetics, we were able to assess the microdeletion architecture in more than 1,000 patients with Genetic Generalized Epilepsy (GGE) compared to more than 5,000 controls. We found that microdeletions occur almost twice as often in GGE patients compared to controls, an analysis that revealed both known suspects and interesting candidates. Continue reading

Flickering lights, endophenotypes, and EEG genetics – CHD2 in photosensitivity

Heritable. Many epilepsy syndromes have signature EEG traits, and these traits are thought to have a strong genetic component. The endophenotype concept suggests that using these epilepsy-related traits in genetic studies will facilitate gene discovery, a concept that has failed us so far in epilepsy research, unfortunately. Now, in a recent publication in Brain, we were able to demonstrate that variants in CHD2 predispose to photosensitivity, an abnormal cortical response to flickering light. Finally, after several decades of persisting difficulties, there is some progress in the field of EEG genetics. Continue reading

Hidden neurometabolic disorders – the expanding spectrum of PNPO deficiency

Pyridoxal 5’-phosphate (PLP). PNPO deficiency is a rare neurometabolic disease that presents with severe neonatal epilepsy responsive to pyridoxal phosphate. While the classical clinical presentation is well described, there might be milder versions of this potentially treatable neurometabolic disease that have not been recognized so far. In a recent publication in Brain, the phenotypic spectrum of PNPO deficiency is revisited. In addition to the classical neonatal phenotype, the authors identify patients with later onset and atypical response to pyridoxal phosphate. In addition, they identify a rare, potentially causative PNPO variant that probably gets stuck in most exome filtering pipelines. Continue reading

GPHN deletions in IGE and mutation-dependent recessive inheritance

Bild1Living in Cologne is a little tough at the moment. Currently, we are in the middle of the Cologne Carnival, the world’s oldest carnival, which started in 1829. Until the upcoming Wednesday the entire city is one big festival. In addition to the 1 million Cologne citizens probably another million tourists will join. Due to this (positive) distraction I will write less than usual. However, I still consider this week’s publications noteworthy. Continue reading

The familial risk of epilepsy – revisited

Missing heritability. The concept of missing heritability is often invoked to demonstrate that existing genetic techniques only identify a fraction of the overall genetic risk for human diseases including the epilepsies. This statement implicitly assumes that we have a good and solid understanding of what the magnitude of genetic risk actually is. However, when looking at the epidemiological studies that have investigated familial risk of epilepsy, some of these studies have inherent problems, including small sample sizes, different phenotype definitions, recruitment bias, and lack of controls. A recent study in Brain now reassesses the familial risk of epilepsy in a population-based cohort of the Rochester Epidemiology Project. There are few instant classics in the field of epilepsy genetics – this study is one of them. Continue reading