Dataset Information

Epi4K: Gene Discovery in 4,000 Epilepsy Genomes

ABSTRACT:

The Epi4K project began in 2011 as an international, multi-center study that seeks to identify and characterize the genetic bases of complex epilepsies. The Center without Walls Epi4K project includes three cores and four scientific projects, as well as a steering committee comprised of the primary study investigators and representatives from the National Institute of Neurological Disorders and Stroke (NINDS). The three cores include: (1) The Administrative Core which handles the overall coordination of Epi4K activities; (2) The Sequencing, Biostatistics and Bioinformatics Core which is responsible for generating the next-generation sequence data, inferring the genetic variation in each of the study participants, and performing the primary analyses to identify epilepsy genes; and (3) The Phenotyping and Clinical Informatics Core which verifies and archives all the phenotypic data from each study participant. The proposed number of patients to be sequenced and analyzed in the scientific projects is a minimum of 4,000; thus the Center was named "Epi4K: Gene Discovery in 4,000 Genomes".

Project 1 addresses the genetics of rare and severe childhood epilepsies, including epileptic encephalopathies (infantile spasms and Lennox-Gastaut syndrome), and malformations of cortical development (periventricular nodular heterotopia and polymicrogyria). Exome and genome sequence data generated from DNA collected from patients will be screened for mutations (single nucleotide substitutions, small insertion-deletions, and copy number variations) that cause or contribute to the diseases. Project 2 is focused on genetic discovery in multiplex families. This study will use next-generation sequencing to identify genomic variation that influences risk for common subtypes of epilepsy including idiopathic generalized epilepsy and nonlesional focal epilepsy. Project 3 seeks to identify genetic determinants of prognosis in patients with a range of epilepsy disorders. This study will study established epilepsy cohorts with well-characterized data on seizure outcome to look for relationships between genetic variation and pharmacological control of seizures. Project 4 will use next-generation sequencing data (exome and genome) to screen for epilepsy-associated copy number variation across all Epi4K projects using novel computational algorithms.

PROVIDER: phs000653.v1.p1 | EGA |

REPOSITORIES: EGA

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Publications

De novo mutations in epileptic encephalopathies.

Allen Andrew S AS Berkovic Samuel F SF Cossette Patrick P Delanty Norman N Dlugos Dennis D Eichler Evan E EE Epstein Michael P MP Glauser Tracy T Goldstein David B DB Han Yujun Y Heinzen Erin L EL Hitomi Yuki Y Howell Katherine B KB Johnson Michael R MR Kuzniecky Ruben R Lowenstein Daniel H DH Lu Yi-Fan YF Madou Maura R Z MR Marson Anthony G AG Mefford Heather C HC Esmaeeli Nieh Sahar S O'Brien Terence J TJ Ottman Ruth R Petrovski Slavé S Poduri Annapurna A Ruzzo Elizabeth K EK Scheffer Ingrid E IE Sherr Elliott H EH Yuskaitis Christopher J CJ Abou-Khalil Bassel B Alldredge Brian K BK Bautista Jocelyn F JF Berkovic Samuel F SF Boro Alex A Cascino Gregory D GD Consalvo Damian D Crumrine Patricia P Devinsky Orrin O Dlugos Dennis D Epstein Michael P MP Fiol Miguel M Fountain Nathan B NB French Jacqueline J Friedman Daniel D Geller Eric B EB Glauser Tracy T Glynn Simon S Haut Sheryl R SR Hayward Jean J Helmers Sandra L SL Joshi Sucheta S Kanner Andres A Kirsch Heidi E HE Knowlton Robert C RC Kossoff Eric H EH Kuperman Rachel R Kuzniecky Ruben R Lowenstein Daniel H DH McGuire Shannon M SM Motika Paul V PV Novotny Edward J EJ Ottman Ruth R Paolicchi Juliann M JM Parent Jack M JM Park Kristen K Poduri Annapurna A Scheffer Ingrid E IE Shellhaas Renée A RA Sherr Elliott H EH Shih Jerry J JJ Singh Rani R Sirven Joseph J Smith Michael C MC Sullivan Joseph J Lin Thio Liu L Venkat Anu A Vining Eileen P G EP Von Allmen Gretchen K GK Weisenberg Judith L JL Widdess-Walsh Peter P Winawer Melodie R MR

Nature 20130811 7466

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the ...[more]

PMID: 23934111

Publication: 1/2

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Project description:The Epi4K project began in 2011 as an international, multi-center study that seeks to identify and characterize the genetic bases of complex epilepsies. The Center without Walls Epi4K project includes three cores and four scientific projects, as well as a steering committee comprised of the primary study investigators and representatives from the National Institute of Neurological Disorders and Stroke (NINDS). The three cores include: (1) The Administrative Core which handles the overall coordination of Epi4K activities; (2) The Sequencing, Biostatistics and Bioinformatics Core which is responsible for generating the next-generation sequence data, inferring the genetic variation in each of the study participants, and performing the primary analyses to identify epilepsy genes; and (3) The Phenotyping and Clinical Informatics Core which verifies and archives all the phenotypic data from each study participant. The proposed number of patients to be sequenced and analyzed in the scientific projects is a minimum of 4,000; thus the Center was named "Epi4K: Gene Discovery in 4,000 Genomes". Project 1 addresses the genetics of rare and severe childhood epilepsies, including <a href="study.cgi?study_id=phs000654">epileptic encephalopathies</a> (infantile spasms and Lennox-Gastaut syndrome), and malformations of cortical development (<a href="study.cgi?study_id=phs001183">periventricular nodular heterotopia</a> and polymicrogyria). Exome and genome sequence data generated from DNA collected from patients will be screened for mutations (single nucleotide substitutions, small insertion-deletions, and copy number variations) that cause or contribute to the diseases. Project 2 is focused on genetic discovery in <a href="study.cgi?study_id=phs001558">multiplex families</a>. This study will use next-generation sequencing to identify genomic variation that influences risk for common subtypes of epilepsy including idiopathic generalized epilepsy and nonlesional focal epilepsy. Project 3 seeks to identify genetic determinants of prognosis in patients with a range of epilepsy disorders. This study will study established epilepsy cohorts with well-characterized data on seizure outcome to look for relationships between genetic variation and pharmacological control of seizures. Project 4 will use next-generation sequencing data (exome and genome) to screen for epilepsy-associated copy number variation across all Epi4K projects using novel computational algorithms.

Project description:We have characterized two post-translational histone modifications in C. elegans on a genomic scale. Micrococcal nuclease digestion and immunoprecipitation were used to obtain distinct populations of single nucleosome cores, which were analyzed using massively parallel DNA sequencing to obtain positional and coverage maps. Two methylated histone H3 populations were chosen for comparison: H3K4 histone methylation (associated with active chromosomal regions) and H3K9 histone methylation (associated with inactivity). From analysis of the sequence data, we found nucleosome cores with these modifications to be enriched in two distinct partitions of the genome; H3K4 methylation was particularly prevalent in promoter regions of widely-expressed genes while H3K9 methylation was enriched on specific chromosomal arms. For each of the six chromosomes, the highest level of H3K9 methylation corresponds to the pairing center responsible for chromosome alignment during meiosis. H3K9 enrichment at pairing centers appears to be an early mark in meiotic chromosome sorting, occurring in the absence of components required for proper pairing of homologous chromosomes. H3K9 methylation shows an intricate pattern within the chromosome arms, with a particular anti-correlation to regions that display a strong ~10 bp periodicity of AA/TT dinucleotides that is known to associate with germline trancription. By contrast to the global features observed with H3K9 methylation, H3K4 methylation profiles were most striking in their local characteristics around promoters, providing a unique promoter-central landmark for 3903 C. elegans genes and allowing a precise analysis of nucleosome positioning in the context of transcriptional initiation. Keywords: epigenetics Examination of total nucleosome and nucleosomes with 2 different histone modifications in C. elegans. 5 samples are analyzed: 1. total mononucleosome core DNA from C. elegans wild type strain N2, 2. anti-H3K4me2/3 precipitated mononucleosome core DNA from C. elegans wild type strain N2, 3. anti-H3K9me3 precipitated mononucleosome core DNA from C. elegans wild type strain N2, 4. total mononucleosome core DNA from C. elegans mutant strain zim-2(tm-574), 5. anti-H3K9me3 precipitated mononucleosome core DNA from C. elegans mutant strain zim-2(tm-574)

Dataset Information

Epi4K: Gene Discovery in 4,000 Epilepsy Genomes

Publications

De novo mutations in epileptic encephalopathies.

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