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• Primary_DIPG_expression_profiles

  In this study, we used RNA-sequencing gene expression profiling in order to characterize specific phenotypic traits in DIPG. Seventeen primary tumor samples stereotactically biopsied at diagnosis by neurosurgeons in the Necker-Enfants Malades hospital (Paris, France) and snap-frozen for RNA extraction and subsequent poly-A mRNA purification.

  Dataset EGAD00001011080

• H3K27ac ChIP-Seq datasets from human islets in high glucose conditions

  14 ChIP-Seq datasets of H3K27ac in human pancreatic islets from 14 donors, where islets were treated in high (11mM) glucose conditions. Samples IDs HI-129, HI-130, HI-131, HI-132, HI-135, HI-137 and HI-152 were also cultured in low glucose conditions.

  Dataset EGAD00001005204

• Next Generation Mendelian Genetics: Neonatal Diabetes

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Neonatal diabetes mellitus (ND) is a rare form of monogenic diabetes (90,000-260,000 live births) that is diagnosed in the first 6 months of life. The disease has been classified as transient or permanent and although it can be inherited, more frequently is sporadic as a result of 'de novo' mutations. Defects in 12 genes have been found as responsible for the disease (defects in the paternally imprinted chromosomal region 6q24, IPF1, SLCA2A, INS, EIF2AK3, GCK, FOXP3, GLIS3, PTF1A, HNF1Beta, KCNJ11 and ABCC8). The two subunits of the ATP-sensitive K channel (ABCC8 and KCNJ11) and the insulin gene (INS), account for almost half of the cases and similar to CHI, the other half, remains genetically unexplained. We became part of this study when we submitted 4 DNA samples for exome sequencing, from patients with NDM of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations or genetic variants in new genes.

  Study phs000542

• SNPs and Extent of Atherosclerosis (SEA) Study

  The SEA study is a genome-wide association study to identify genetic variants associated with premature atherosclerosis in subjects included in the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) repository - a unique NHLBI resource including data, DNA and arterial specimens from over 3000 multi-ethnic subjects 15-34 years of age who died of non-atherosclerotic causes (mostly trauma). All PDAY subjects had post-mortem quantitative assessment of raised atherosclerotic lesions in their aorta and coronary arteries - making this the largest and most carefully phenotyped cohort for premature atherosclerosis in the world. The goal of the current project was to use the quantitative measure of raised atherosclerotic lesions in the PDAY cohort as the target phenotype for a genome-wide association study and to use quantitative measures of subclinical atherosclerosis (coronary calcium and carotid IMT) in the Multi-Ethnic Study of Atherosclerosis (MESA) to confirm or refute candidate loci identified from the PDAY analysis. Identifying genetic factors that predispose individuals to premature atherosclerosis could lead to more effective screening and early treatment of high risk individuals and suggest novel molecular targets for treatment and prevention interventions.

  Study phs000349

• Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma Pathology

  ​​Multiple Myeloma (MM) develops from well-defined precursor stages known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering MM (SMM); however, invasive bone marrow (BM) biopsy limits screening and monitoring strategies for patients. In this study, we enumerated circulating tumor cells (CTCs) from patients with precursor and overt diseases, and developed a novel approach, MinimuMM-seq, which enables detection of translocations and copy number abnormalities through whole-genome sequencing of highly pure CTCs. In a cohort of 51 patients, 24 with paired BM, we applied our method MinimuMM-seq and detected 100% of clinically reported BM biopsy events. The next-generation sequencing (NGS) assay could replace molecular cytogenetics by Fluorescence In Situ Hybridization (FISH) for diagnostic yield and risk classification. In 8 patients we could apply MinimuMM-seq on serially collected samples to track and monitor major clones in peripheral blood. We describe clonal evolution and shifting dynamics of subclones over time, as well as in between blood and marrow compartments. All whole-genome sequencing (WGS) data generated in this study will be made accessible through dbGaP.

  Study phs003084

• NHLBI Recipient Epidemiology Donor Evaluation Study (REDS)-III - Brazil Sickle Cell Disease Cohort (REDS-BSCDC)

  The Recipient Epidemiology and Donor Evaluation Study (REDS)-III program established a Brazilian Sickle Cell Disease (SCD) Cohort to identify molecular determinants of response to transfusions, alloimmunization and risk factors associated with HIV infection. The Brazil population presents a complex admixture of African, European, Asian and Indigenous heritage and will provide insights into genetic, demographic, social, and healthcare system determinates of SCD outcomes. The REDS-III Brazil SCD cohort began in the Fall of 2013 and aimed to: Establish a cohort of SCD patients with a comprehensive centralized electronic database of detailed clinical, laboratory and transfusion information, as well as establish a repository of blood samples to support biological studies relevant to SCD pathogenesis and transfusion complications; Characterize changes in markers of inflammation in response to transfusion by analyzing chemokine/cytokine panels in serial post transfusion specimens; Identify single nucleotide polymorphisms (SNPs) that contribute to the risk of red blood cell alloimmunization in SCD by performing a genome-wide association (GWA) study in transfused SCD patients; Characterize risk of HIV and HIV outcomes in the Brazilian SCD population and compare SCD outcomes among HIV sero-positive and sero-negative SCD patients.

  Study phs001972

• Effective screening strategy for deafness using a new-genetation sequencing platform: a consecutive analysis

  The diagnosis of the genetic etiology of deafness contributes to the clinical management of patients. We performed the following four genetic tests in three stages for 52 consecutive deafness subjects in one facility. We used the Invade assay and Sanger sequencing for the GJB2 gene or SLC26A4 gene in the first stage test, TaqMan genotyping assay in second stage test, and targeted exon sequencing using the massively parallel DNA sequencing in third stage test. Overall, we identified the genetic cause in 40% (21/52) of patients. The diagnostic rates of the first-, second- and third-stage genetic testing were 17%(9/52), 9%(4/43) and 21% (8/39), respectively. The combination approach using these genetic tests appears to be useful as a diagnostic tool for deafness patients. We recommended that genetic testing for the screening of common mutations in deafness genes using the Invader assay or TaqMan genotyping assay be performed as the initial evaluation. For the remaining undiagnosed cases, targeted exon sequencing using MPS is clinically and economically beneficial. This data set was MPS reads data (fastq) for 39 sensorineural hearing loss patients.

  Study JGAS000032

• Field_effect_of_healthy_and_diseased_livers_WGS

  Recent work in the Campbell group has revealed somatic mutations present in normal, non-cancerous human skin. A subset of the mutations conferred selective advantages to the host cells, leading to clonal expansions and raising the risk for future cancer development. Capturing such somatic mutations in normal tissue is important to advance our understanding about carcinogenesis and could provide prospective medical insights. In this project, our goal is to detect somatic mutations in normal (pre-cancerous) liver tissue. Using Laser Microdissection technology, we will dissect individual liver lobules from patient samples and submit these to sequencing. For each patient sample, we aim to sequence multiple lobules to characterise the mutagenic burden. Samples will be taken from patients with different liver disease aetiologies, including alcoholism and obesity, with a view on distinguishing the prevalent mutation types occurring in each disease context. We will perform both whole genome and targeted sequencing, initially using the WTSI cancer panel. Later we aim to use a novel bait set that captures both cancer genes as well as genes relevant to the non-cancerous samples (ie. genes implicated in hereditary disorders, immune sequences).

  Study EGAS00001002413

• SHANK2 mutations associated with Autism Spectrum Disorder cause hyperconnectivity of human neurons

  Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). To investigate their effect on synaptic connectivity, we generated cortical neurons from induced pluripotent stem cells (iPSC) derived from neurotypic and ASD-affected donors. We developed Sparse coculture for Connectivity (SparCon) assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed striking increases in dendrite length, dendrite complexity, total synapse number, and frequency of spontaneous excitatory postsynaptic currents. These findings were phenocopied in gene-edited homozygous SHANK2 knockout cells and rescued by gene correction of an ASD SHANK2 muation, supporting a role for SHANK2 as a regulator of connectivity in developing human neurons. Dendrite length increases were exacerbated by IGF1, TG003, or BDNF, and suppressed by DHPG treatment. The transcriptome in these isogenic SHANK2 neurons was deeply perturbed in synapse, plasticity, and neuronal morphogenesis gene sets and ASD gene modules, and activity-dependent dendrite extension was impaired. Our unexpected findings provide evidence for hyperconnectivity and profoundly altered transcriptome in SHANK2 neurons derived from ASD subjects.

  Study EGAS00001003436

• Reference Exome Data for a Northern Brazilian population

  Whole exome sequencing (WES) is a popular technology widely used in the diagnosis of rare genetic diseases and provides useful variant data for analysis of complex diseases. However, there is not always adequate population-specific reference data available to assist clinical geneticists in assigning a diagnostic variant to a specific clinical condition. Here we provide a catalogue of variants called after sequencing the exomes of 45 babies from the State of Rio Grande do Nord in Brazil. Sequence data were processed using an ‘intersect-then-combine’ (ITC) approach, using GATK and SAMtools to call variants. A total of 612,761 variants were identified in at least one individual in this Brazilian Cohort, including 559,448 single nucleotide variants (SNVs) and 53,313 insertion/deletions. Of these, 58,111 overlapped with nonsynonymous (nsSNVs) or splice site (ssSNVs) SNVs in dbNSFP. As an aid to clinical diagnosis of rare diseases, we used the American College of Medicine Genetics and Genomics (ACMG) guidelines to assign pathogenic/likely pathogenic status to 439 (0.755%) of the 58,111 nsSNVs and ssSNVs. Our data set provides a useful reference point for diagnosis of rare diseases in Brazil.

  Study EGAS00001004112

• Whole genome sequencing of Ewings Sarcoma

  Sarcomas are cancers of the bone and soft tissue often defined by their gene fusions. However, the timing, context, and processes by which these pathogenic fusions arise are unknown. We explored this in Ewing sarcoma, a cancer driven by EWSR1-ETS fusions, with very few cooperating mutations. Combining whole-genome sequencing with enhanced informatics, we found that the EWSR1-ETS fusion arose from striking rearrangement clusters in 42% of cases (52/124). Notably, these were organized in loops that universally contained the fusion at their center, while also weaving up to 18 genes together with it. We found the same pattern of rearrangements in three additional types of sarcoma. From these data, we define a new signature for sarcoma fusions that precedes other somatic changes, in the earliest replicating DNA of the genome. This dramatic, sudden process impinges on many genes – generating multiple coding changes that profoundly affect the transcriptome, with the disease-defining gene fusion at its core. These rearrangement loops emerge in an early ES clone from which both the primary tumor and the lethal relapse emerged, and then evolved in parallel until clinically detected.

  Study EGAS00001003385

• The demographic history and mutational load of African hunter-gatherers and farmers

  The distribution of deleterious genetic variation across human populations is a key issue in evolutionary biology and medical genetics. However, the impact of different modes of subsistence on recent changes in population size, patterns of gene flow, and deleterious mutational load remains unclear. Here, we report high-coverage exomes from various populations of rainforest hunter-gatherers and farmers from central Africa. We find that the recent demographic histories of hunter-gatherers and farmers differed considerably, with population collapses for hunter-gatherers and expansions for farmers, accompanied by increased gene flow. We show that purifying selection against newly arising deleterious alleles is of similar efficiency across African populations, in contrast with Europeans where we detect weaker purifying selection. Furthermore, the per-individual mutation load of rainforest hunter-gatherers is similar to that of farmers, under both additive and recessive models. Our results indicate that differences in the cultural practices and demographic regimes of African populations have not resulted in large differences in mutational burden, and highlight the beneficial role of gene flow in reshaping the distribution of deleterious genetic variation across human populations.

  Study EGAS00001002457

• Ewings Sarcoma RNA-Seq

  Sarcomas are cancers of the bone and soft tissue often defined by their gene fusions. However, the timing, context, and processes by which these pathogenic fusions arise are unknown. We explored this in Ewing sarcoma, a cancer driven by EWSR1-ETS fusions, with very few cooperating mutations. Combining whole-genome sequencing with enhanced informatics, we found that the EWSR1-ETS fusion arose from striking rearrangement clusters in 42% of cases (52/124). Notably, these were organized in loops that universally contained the fusion at their center, while also weaving up to 18 genes together with it. We found the same pattern of rearrangements in three additional types of sarcoma. From these data, we define a new signature for sarcoma fusions that precedes other somatic changes, in the earliest replicating DNA of the genome. This dramatic, sudden process impinges on many genes – generating multiple coding changes that profoundly affect the transcriptome, with the disease-defining gene fusion at its core. These rearrangement loops emerge in an early ES clone from which both the primary tumor and the lethal relapse emerged, and then evolved in parallel until clinically detected.

  Study EGAS00001003062

• Comparative transcriptome of CD34+ hematopoietic progenitors from myeloproliferative patients and control donors

  BCR-ABL-negative MPNs are related to mutations activating the JAK2/STAT pathway and occurring in hematopoietic stem cells (HSC). The most prevalent mutation is JAK2V617F. Calreticulin (CALR) and activating MPLW515 mutations are also observed in ET and PMF. Additional non-MPN mutations may be found, particularly in PMF, and can change disease phenotype or accelerate progression to myelofibrosis or leukemia. In this study, we wanted to compare the transcriptome of CD34+ progenitors from JAK2V617F postive MPN patients to the CD34+ progenitors from control donors. The patients were selected for their high JAK2V617F variant allele frequency (from 60 to 100% VAF). Peripheral blood from patients was collected in EDTA tubes. Hematopoietic progenitors (CD34+) were isolated from mononuclear cells (MNCs) by immunomagnetic enrichment (Miltenyi, Biotech) and were amplified for 5 days in serum-free medium in the presence of a cocktail of human recombinant cytokines containing EPO (1 U/mL) (Amgen Thousand Oaks, CA), TPO (20 ng/mL) (Kirin, Japan), SCF (25 ng/mL) (Biovitrum AB, Sweden), IL-3 (10 ng/mL), FLT3-L (10 ng/mL), G-CSF (20 ng/mL) and IL-6 (100 U/mL) (MiltenyiBiotec).

  Study EGAS00001005106

• Germline biallelic mutation affecting the transcription factor Helios causes pleiotropic defects of immunity

  We studied a patient with recurrent respiratory infections and hypogammaglobulinemia and identified a germline homozygous missense mutation in IKZF2 encoding Helios (p.Ile325Val). We show that HeliosI325V retains DNA-binding and dimerization properties, but loses interaction with several partners, including epigenetic remodelers HDAC1, HDAC3 and the ATAC complex. Single-cell RNA-sequencing of peripheral blood mononuclear cells revealed gene expression signatures indicative of a shift towards pro-inflammatory, effector-like status in the patient’s T cells. We observed an upregulation of the anti-inflammatory gene, TSC22D3, encoding the glucocorticoid-induced leucine zipper (GILZ), whose expression was reported to increase upon IL-2 deprivation. We validated this finding in primary T cells, where we observed a pronounced reduction in IL-2 production upon their stimulation, together with a defect in their ability to proliferate, rendering them more anergic. Collectively, we identify a novel germline-encoded inborn error of immunity and define a role for Helios in conventional T cells, whereby interactions with specific binding partners is necessary to mediate the transcriptional programs that enable T-cell homeostasis in health and disease.

  Study EGAS00001005675

• Identification of Germline Monoallelic Mutations in IKZF2 in Patients with Immune Dysregulation.

  Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3, encoding Ikaros and Aiolos, have recently been identified in patients with phenotypically similar immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p.R291X)- and 4 distinct missense variants) in six patients with systemic lupus erythematosus, immune thrombocytopenia or EBV-associated hemophagocytic lymphohistiocytosis. Patients exhibited hypogammaglobulinemia, decreased number of T-follicular helper and NKcells. Single-cell RNA sequencing of PBMCs from the patient carrying the R291X variant revealed upregulation of pro-inflammatory genes associated with T-cell receptor activation and T-cell exhaustion. Functional assays revealed the inability of HeliosR291X to homodimerize and bind target DNA as dimers. Moreover, proteomic analysis by proximity-dependent Biotin Identification revealed aberrant interaction of 3/5 Helios mutants with core components of the NuRD complex conveying HELIOS mediated epigenetic and transcriptional dysregulation.

  Study EGAS00001005874

• Patient-tailored design for selective co-inhibition of leukemic cell subpopulations

  The extensive primary and secondary drug resistance in many cancer types requires rational approaches to design personalized and selective combinatorial therapies that do not only show synergistic effect in overall cancer cell killing but also result in minimal toxic side effects on non-malignant cells. To address the combinatorial explosion in the number of relevant combinations, we implemented a machine learning approach that prioritizes patient-customized drug combinations with a desired synergy-efficacy-toxicity balance by combining single-cell RNA-sequencing with ex vivo single-agent testing in scarce patient-derived primary cells. When applied to two diagnostic and two refractory AML patient cases, each with a different genetic background, our integrated approach accurately predicted patient-specific combinations that were shown to result not only in synergistic cancer cell co-inhibition but were also capable of targeting specific AML cell subpopulations that emerge in differing stages of disease pathogenesis or treatment regimens. Our data-driven approach provides an unbiased means for systematic identification of personalized combinatorial regimens that selectively co-inhibit leukemic cells while avoiding inhibition of non-malignant cells, and highlight the relevance of considering cell heterogeneity for personalized cancer therapy.

  Study EGAS00001004614

• DNA methylation landscape of prostate cancer

  Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy thanks to improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles are associated with the mutually exclusive SPOP mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of 42 patients with prostate cancer brain metastases (PCBM), with matched primary samples available for 17 patients, we carried out DNA methylation analysis using Illumina EPIC array. We examined the epigenetic distinction between primary PCa and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM in particular. Multiregion sampling of PCBM revealed epigenetic heterogeneity in metastases. We found aberrant methylation in PCBM is associated with mutational background, PRC2 complex activity and upregulation of EZH2, an effect that is particularly pronounced in SPOP mutant PCBM. While we detected a hypermethylator phenotype in PCBM, we also observed hypomethylation occurring at the promoters of genes involved in neuroactive ligand-receptor interactions or the calcium signalling pathway, such as GABRB3 and GRM5, a change not observed in non-brain prostate cancer metastases.

  Study EGAS00001006670

• Pre-activated anti-viral innate immunity in the upper airways controls early SARS-CoV-2 infection in children

  Children have reduced SARS-CoV-2 infection rates and a substantially lower risk for developing severe COVID-19 than adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here, we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n=18) and age-matched SARS-CoV-2–positive children (n=24) and corresponding samples from adults (n=44), covering an age range of four weeks to 77 years. Children displayed higher basal expression of the relevant pattern recognition receptors (PRR) such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages, and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)+ cytotoxic T cells and a CD8+ T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral responses to SARS-CoV-2 infection than adults.

  Study EGAS00001005461

• SINGLE-CELL RNA SEQUENCING Single-cell RNA sequencing was performed on 13 ‘mild-moderate’ and 10 ‘critical’ COVID19 PBMC samples

  Summary Epidemiological and clinical reports have indicated that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we performed cytokine and multiplex immune profiling in mild-moderate and critically ill COVID-19 patients. Hypercytokinemia in COVID-19 differed from the IFN-γ-driven cytokine storm in macrophage activation syndrome, and was more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling showed that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Expression of antigen presenting machinery was also reduced in critical disease. Furthermore, we found that neutrophils contributed to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together these findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

  Study EGAS00001005039

• DIS3 licenses B cells for physiological plasma cell differentiation in humans

  DIS3 licenses B cells for physiological plasma cell differentiation in humans

  Study EGAS50000000853

• IDH1 Somatic Mutation Profile in Intrahepatic Cholangiocarcinoma

  The objective of this study is to identify somatic IDH1 mutations in intrahepatic cholangiocarcinoma samples.

  Study EGAS50000001638

• RNASeq files for Roussel MBPRP

  RNASeq files for Roussel paper titled "Combination of CDK4/6 with BET-bromodomain and PI3K/mTOR inhibitors in medulloblastoma in vitro and in vivo"

  Dataset EGAD00001008842

• BS-seq in plasma of CRC patients

  We performed whole genome bisulfite sequencing of plasma DNA in 11 colorectal cancer patients to study the colonic DNA in plasma.

  Dataset EGAD00001004568

• Identification and Molecular Characterization of Somatic Mutations in Malformations of Cortical Development

  Genetic mutations causing disease may be inherited, newly acquired in parental gametes and present in the zygote or acquired as somatic events at some point in development after fertilization. The burden and localization of an acquired mutation depend on when the mutation arises. As is the case for inherited genetic variation, there is accumulating evidence that somatic mutations can lead to severe tissue-specific disease. Malformations of cortical development (MCD) represent a group of disorders characterized by a range of morphological and structural abnormalities of the cerebral cortex reflecting errors in embryonic cortical development. MCD are associated with intellectual disability, as well as refractory epilepsy, and may require the surgical removal of the affected tissue. Inherited gene mutations involved in neuronal development explain only a fraction of MCD cases. In this project we sought to evaluate the hypothesis that somatic mutations disrupt embryonic cortical development and are responsible for a substantial fraction of MCD. Using high coverage next generation sequencing of protein-coding regions in DNA extracted from abnormal brain tissue and unaffected tissue (leukocytes) from patients with three forms of MCD, we sought to identify somatic mutations within each patient with MCD. Exome sequence data from study participants are provided to facilitate research into the genetic underpinnings of MCD.

  Study phs002128