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

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