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
Tag Archives: IGE/GGE
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
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 Ih current. 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
The GABA link in Genetic Generalized Epilepsy
GGE. The Genetic Generalized Epilepsies (GGE) are common epilepsies in children and adults with a prominent genetic contribution. However, genetic risk factors for GGE have been more difficult than most researchers would have expected to pin down. Genome-wide association studies for common variants and association studies for ultra-rare variants have been able to identify several candidate genes, but much of the genetic risk for GGE remain unaccounted for. In a recent study in Lancet Neurology, we have tried a different approach to address the genetic contribution for GGE, looking at gene groups rather than single genes. Using this approach, we were able to detect a signal that would not have been found when looking at individual genes alone, a contribution of rare variants in genes for GABA-A receptors that reliably spans across three different cohorts. 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
