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

Speech dyspraxia and dysarthria – the other side of GRIN2A

GRIN2A. Mutations in several genes coding for NMDA receptor subunits have recently been found in various neurodevelopmental disorders. Amongst the different genes, GRIN2A is one of the most prominent ones and mutations in this gene are found in patients with epilepsy-aphasia syndromes. So far, we have mainly looked at GRIN2A from the epilepsy side. In a recent publication in Neurology, Turner and collaborators now examine the speech phenotype in GRIN2A families. They examine two families where speech issues are a prominent phenotypic feature. It turns out that GRIN2A mutations may predispose to a distinct speech phenotype. Continue reading

SETBP1, ZMYND11, and the power of joint exome and CNV analysis

Parallel worlds. There are two fields of genetics for neurodevelopmental disorders that currently produce large amounts of data – the field of copy number variation analysis and the field of exome sequencing. When assigning pathogenicity, information from both genetic technologies are rarely considered jointly. A recent study in Nature Genetics now performs a combined analysis of a large CNV and exome datasets in intellectual disability and autism. Interestingly, this method produces robust results, highlighting novel causative genes. Continue reading

Publications of the week – 15q13.3 deletions, POLG1 and liver failure, and twins

Update. In the last few weeks, we have tried to catch up with some recent publications in the field that mainly focused on autism spectrum disorder. This week’s publications, in contrast, cover a wide range of topics including the phenotypic spectrum of the 15q13.3 microdeletions, the importance of POLG1 in valproate-induced liver failure, and the most recent updates on epilepsy and twins. Continue reading

Publications of the week – PRICKLE1, Phelan-McDermid syndrome, and mitochondrial genetics

The week in review. It’s currently a bit quiet in the literature with respect to novel gene findings. However, there is plenty to explore about genes and variants we already know and their role in human epilepsy. This week’s selection of publications is about functional studies in a gene for progressive myoclonus epilepsy, the EEG signature in a microdeletion syndrome, and contribution of mitochondrial genetics in intractable epilepsy. Continue reading

Copy number variations and the forgotten epilepsy phenotypes

Complexity. Structural genomic variants or copy number variations (CNV) are known genetic risk factors for various epilepsy syndromes. In fact, CNVs might represent the single most studied type of genetic alterations across a very broad range of epilepsy syndromes. There is, however, a group of patients that is usually not investigated in genetic studies: patients with presumable lesional epilepsies or questionable findings on Magnetic Resonance Imaging (MRI). Many of these epilepsies are usually thought to be secondary to the identified lesion, and genetic risk factors are not considered.  In a recent study in the European Journal of Human Genetics last week, we investigated the role of CNVs in a cohort of patients with complex epilepsy phenotypes that were not easily classified into existing categories. Many of patients included had definite or questionable findings on MRI.  The results of our study made us wonder whether the boundary between lesional and genetic epilepsies needs to redrawn. Continue reading

SHANK3, epilepsy, and the excitatory/inhibitory imbalance

Postsynaptic. SHANK proteins are elements of the postsynaptic density, linking synaptic transmission with the cytoskeleton. Deletions in SHANK2 and SHANK3 are known genetic risk factors for a broad range of neurodevelopmental disorders. The role of the reciprocal duplications, however, has remained unclear. In recent paper in Nature, a novel mouse model expressing a SHANK3 transgene is investigated. The results of a mere 1.5 fold overexpression of the protein are dramatic, hinting at unanticipated mechanisms that regulate the balance between excitation and inhibition.  Continue reading

The mosaic brain – single neuron copy number variations in humans

Variability. It has been rumored for quite some time, but only now is solid evidence present to show this phenomenon: the high degree of genomic diversity of human neurons. In a recent paper in Science, the genomic diversity among frontal brain neurons is explored on a cell-by-cell basis. The results are breathtaking: up to 40% of frontal cortex neurons have altered genomic material affected by large deletions or duplications. This study provides the linchpin for a plethora of new investigations aiming to understand the impact of this phenomenon in health and disease. Continue reading

C6orf70, neuronal migration and periventricular heterotopia

Radial migration. The fact that neurons find their place in the cortex during development is nothing short of a miracle. Many neurons originate in the subventricular zone, i.e. the area lining the ventricles. During brain development, these neurons subsequently climb outwards to their final positions using radial glia cells as scaffolds. If this delicate process is disturbed, neurons may be misplaced. Periventricular nodular heterotopia (PVNH) is a condition in which defects in neuronal migration result in ectopic neuronal nodules lining the ventricles. These nodules may result in a broad range of epilepsies, ranging from mild seizure disorders to intractable epilepsy with intellectual disability. Many cases of PVNH are assumed to be genetic, and FLNA and ARFGEF2 as known causative genes. However, the cause remains unknown in a significant number of patients. In a recent paper in Brain, C6orf70 is identified as a new candidate for PVNH using a clever combination of array CGH and exome sequencing. Continue reading

16p13.11 microdeletions and the male bias

The enigmatic deletion. Amongst the various microdeletions implicated in human epilepsy, the 16q13.11 microdeletion is one of the structural variations that poses significant difficulties in understanding its associated risk and phenotypes. Now a recent paper in PLOS One investigates a large cohort of patients with various neurodevelopmental disorders for microdeletions in the 16p13.11 region. And particularly the finding regarding the sex distribution of symptomatic deletion carriers is remarkable.   Continue reading