Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

Epilepsy is a common and serious neurologic disease with a strong genetic component. Genetic studies have identified an increasing collection of disease-causing genes. The impact of these genetic discoveries is wide reaching-from precise diagnosis and classification of syndromes to the discovery and validation of new drug targets and the development of disease-targeted therapeutic strategies. About 25% of genes identified in epilepsy encode ion channels. Much of our understanding of disease mechanisms comes from work focused on this class of protein. In this study, we review the genetic, molecular, and physiologic evidence supporting the pathogenic role of a number of different voltage- and ligand-activated ion channels in genetic epilepsy. We also review proposed disease mechanisms for each ion channel and highlight targeted therapeutic strategies.

https://pharmrev.aspetjournals.org/content/pharmrev/70/1/142.full.pdf

Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies.

Epilepsy is a group of disorders characterized by recurrent seizures, and is one of the most common neurological conditions. The genetic basis of epilepsy is clear from epidemiological studies and from rare gene discoveries in large families. The three major classes of epilepsy disorders are genetic generalized, focal and encephalopathic epilepsies, with several specific disorders within each class. Advances in genomic technologies that facilitate genome-wide discovery of both common and rare variants have led to a rapid increase in our understanding of epilepsy genetics. Copy number variant and genome-wide association studies have contributed to our understanding of the complex genetic architecture of generalized epilepsy, while genetic insights into the focal epilepsies and epileptic encephalopathies have come primarily from exome sequencing. It is increasingly clear that epilepsy is genetically heterogeneous, and novel gene discoveries have moved the field beyond the known contribution of ion channels to implicate chromatin remodeling, transcriptional regulation and regulation of the mammalian target of rapamycin (mTOR) protein in the etiology of epilepsy. Such discoveries pave the way for new therapeutics, some of which are already being studied. In this review, we discuss the rapid pace of gene discovery in epilepsy, as facilitated by genomic technologies, and highlight several novel genes and potential therapies.

/pdf/advancing-epilepsy-genetics-in-the-genomic-era-4p1w9o0ax6.pdf

Advancing epilepsy genetics in the genomic era

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.

The intrinsic electrical characteristics of different types of neurons are shaped by the K+ channels they express. From among the more than 70 different K+ channel genes expressed in neurons, Kv3 f...

/pdf/kv3-channels-enablers-of-rapid-firing-neurotransmitter-454jb1rchv.pdf

Kv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance

Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo mutation, c.959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes KV3.1, a subunit of the KV3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and SERPINI1). Identification of mutations in PRNP, SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity.

A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

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A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy