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• RNA-seq as a tool for evaluating human embryo competence

  The majority of embryos that are created through IVF do not implant. It seems plausible that rates of implantation would improve if we had a better understanding of molecular factors affecting embryo competence. Currently, the process of selecting an embryo for uterine transfer utilizes an ad-hoc combination of morphological criteria, the kinetics of development, and genetic testing for aneuploidy. However, no single criterion can ensure selection of a viable embryo. In contrast, RNA-sequencing of embryos could yield highly dimensional data, which may provide additional insight and illuminate the discrepancies among current selection criteria. Indeed, recent advances enabling the production of RNA-sequencing (RNA-seq) libraries from single cells have facilitated the application of this technique to the study of some transcriptional events in early human development. However, these studies have not assessed the quality of their constituent embryos relative to commonly used embryological criteria. Here, we perform proof-of-principle advancement to clinical selection procedures by generating high quality RNA-seq libraries from a trophectoderm biopsy as well as the remaining whole embryo. We combine state-of-the-art embryological methods with low-input RNA-seq to develop the first transcriptome-wide approach for use in future predictive embryology studies. Specifically, we demonstrate the capacity of RNA-seq as a promising tool in preimplantation screening by showing that biopsies of an embryo can capture valuable information content available in the whole embryo from which they are derived. Furthermore, we show that this technique can be used to generate a RNA-based digital karyotype, and to identify candidate competence-associated genes. Together, these data establish the foundation for a future RNA-based diagnostic in IVF.

  Dataset EGAD00001005044

• Vanderbilt Genome-Electronic Records (VGER) Project: QRS Duration

  An important potential enabling resource for Personalized Medicine is the combination of a DNA repository with Electronic Medical Record (EMR) systems sufficiently robust to provide excellence in clinical care and to serve as resources for analysis of disease susceptibility and therapeutic outcomes across patient populations. The Vanderbilt EMR is a state of the art clinical and research tool (that includes >1.7 million records), and is associated with a DNA repository which has been in development for over 3 years; these are the key components of VGER, the Vanderbilt Genome-Electronic Records project, a part of NHGRI's eMERGE network. The VGER model acquires DNA from discarded blood samples collected from routine patient care, and can link these to de-identified data extracted and readily updated from the EMR. The phenotype we analyze here is the QRS duration on the electrocardiogram, since slow conduction (indicated by longer QRS duration) is a marker of arrhythmia susceptibility.

  Study phs000188

• Data from the paper Context-specific Effects of TGFβ/SMAD3 in Cancer Are Modulated by the Epigenome. Tufegdzic et al, Cell Reports 2015

  The transforming growth factor beta (TGFβ) signalling pathway exerts opposing effects on cancer cells, acting either as a tumor-promoter or as a tumor-suppressor. Here we show these opposing effects are a result of the synergy between SMAD3, a downstream effector of TGFβ signalling, and the distinct epigenomes of breast tumor initiating cells (BTICs). These effects of TGFβ are associated with distinct gene expression programs, but genomic SMAD3 binding patterns are highly similar in the BTIC-promoting and BTIC- suppressing contexts. Our data show cell type-specific epigenetic configurations provide a modulatory layer by determining accessibility of genes to regulation by TGFβ/SMAD3. LBH, one such context-specific target gene, is regulated according to its DNA methylation status, and is crucial for TGFβ-dependent promotion of BTICs. Overall, these results reveal that the epigenome plays a central and previously overlooked role in shaping the context-specific effects of TGFβ in cancer.

  Study EGAS00001001570

• Identification of Modifiers of 22q11.2 Deletion Syndrome in Whole Genome Sequence - CIDR

  This project aims to identify genetic modifiers of congenital heart disease (CHD), which occurs among 22q11.2 deletion syndrome (22q11.2DS; also known as DiGeorge syndrome/velo-cardio-facial syndrome) patients. In contrast to the prevalence of ~0.8% in the general population, about 60%-70% of 22q11.2DS patients have CHD, of which most are conotruncal heart defects, making 22q11.2DS a very ideal model to study the genetic underpins of CHD. The chromosome 22q11.2 region is susceptible to meiotic chromosome rearrangements leading to hemizygous deletions, because there are large blocks of low copy repeats, termed LCR22s, that are dispersed in the region. Non-allelic homologous recombination during meiosis can lead to specific-sized deletions. Approximately 90% have a typical hemizygous 3 million base pair (Mb) deletion between LCR22-A and -D, while some have nested deletions between LCR22-A and B or LCR22-A and C. Our goal is to perform a case-control association study, in which cases have CHD, while controls have normal heart structures, all with 22q11.2DS. All individuals are unrelated and have been collected from collaborators in the US, Canada and Europe. All subjects received a clinical diagnosis of 22q11.2DS and signed informed consent to allow a blood sample to be collected for research. The DNA samples were de-identified in 2 steps to protect their privacy. We then determined deletion type using multiplex ligation-dependent probe amplification (MLPA). This information is provided for the great majority of subjects. We also obtained cardiac phenotype information from echocardiogram reports as well as reported race and ethnicity (Hispanic vs. non-Hispanic information), which is required for the analysis. We will obtain 30X whole-genome sequence data from NIH CIDR. We will first annotate the sequence variants identified to uncover rare ( For genotype data, we will provide the raw fastq data from whole-genome sequencing as well as the called variants file in a VCF file. For phenotype data, we will provide the sample relationship files (ped files), CHD affection status, deletion type, and race.

  Study phs002514

• Gene mutation and rescue in congenital diaphragmatic hernia

  Congenital Diaphragmatic Hernia (CDH) is a common and life-threatening malformation. The most common phenotype is left-sided posterolateral (Bochdalek-type) hernia accompanied by pulmonary hypoplasia. Due to the high mortality, most of the cases have no family history for CDH. The rare presumed Mendelian instances of CDH have the potential to be extremely informative about the molecular mechanisms generating this phenotype. Three multiplex families were deemed meritorious for study by whole exome sequencing: Parents who were 1st cousins gave birth to 2 children with CDH (one of whom also had cleft lip and palate), both now deceased. A DNA sample was available from one child. We proposed to perform a SNP array to identify regions of homozygosity by descent and intersect these regions with variants detected on exome sequencing. This effort has led to the identification of 3 confirmed variants. We are determining which if any are expressed in the primordial developing diaphragm and are also using bioinformatic approaches to determine which of these candidates interact with known CDH genes. This non-consanguineous couple gave birth to 2 affected boys with an identical and lethal CDH phenotype (consisting of diaphragmatic hernia, epigastric hernia, and facial dysmorphism) and one healthy boy. We predicted X-linked inheritance and findings from X chromosome microsatellite marker analysis are consistent with this. Accordingly, we are focusing on sequence variants mapping to the X chromosome. We have identified a single candidate gene and confirmed that the variant follows an X-linked pattern of inheritance in all family members. Expression studies are underway. These affected males are second cousins. By virtue of their position in the pedigree, we predicted an inheritance pattern consistent with X-linked inheritance. Data from WES and microsatellite marker analysis are currently being integrated.

  Study phs000485

• Kidney_transplant_nephrectomy_scRNAseq

  Single cell transcriptomics study of tissue from human kidney transplant nephrectomies Tissue is acquired from kidney transplant nephrectomies, homogenised and disaggregated to a single cell suspension prior to droplet encapsulation single cell RNAseq (10X protocol) or plate based single cell RNAseq (SS2 protocol). Human tissues, including the kidney are seeded with a tissue resident immune cell network throughout life. These cells may self renew in situ or be replaced by circulating precursors which enter the tissue in response to tissue specific niche and inflammatory signals. We are using single cell RNA sequencing of kidney transplant nephrectomy tissue to 1) understand the immune cell populations which are resident within the human kidney 2) identify which of these populations is donor or recipient derived. 3) Uncover the temporal dynamics of donor/recipient chimerism in the the human kidney following transplantation. 4) Understand transcriptional differences between organs removed for a variety of reasons (infection, chronic rejection, vascular emergencies) This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003935

• Longitudinal snRNAseq and DNAseq of IDHmutant glioma

  We collected longitudinal glioma samples from 35 patients with an IDH-mutant oligodendroglioma (n = 13) or IDH-mutant astrocytoma (n = 22) diagnosis based on 2021 WHO glioma classification at two or three time points (n = 75 samples). For each patient, we designated the two earliest samples as the initial and recurrence for longitudinal analyses. In 17 of 35 longitudinal pairs, the initial sample was obtained at primary diagnosis, whereas the remaining 18 cases the initial samples were collected at a subsequent surgery. Between the initial and recurrence samples, 26 of 35 patients received radiotherapy and/or alkylating chemotherapy, whereas no adjuvant treatment was reported for the remaining patients. To comprehensively investigate IDH-mutant glioma evolution, we used snRNAseq and bulk DNA/RNA sequencing from the same resected glioma samples. A subset of these samples was profiled with simultaneous snRNA-ATAC sequencing (48 out of 75), including 21 matched longitudinal pairs,

  Dac EGAC50000000973

• Rna-Seq Leiomyosarcoma subtypes

  Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyzed 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlighted the extremely early origins of LMS. Three specific subtypes of LMS develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynaecological origin acquired the highest burden of genomic mutation and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP and other DNA damage response inhibitors, suggesting a novel therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis.

  Study EGAS00001004783

• GWAS for Membranous Nephropathy

  Primary membranous nephropathy (MN) is a rare autoimmune cause of kidney failure. This dataset is from a genome-wide association study (GWAS) designed to identify novel genetic risk loci for MN. The provided cohort (named as European-1 Cohort) is composed of 611 cases of primary MN and 1,246 healthy controls of European ancestry. This cohort was used in the GWAS meta-analysis, as described in the manuscript entitled "Genetic architecture of membranous nephropathy and its potential diagnostic implications" (Nature Communications 2020, in press).The genome-wide summary statistics, including trans-ethnic meta-analysis across 8 GWAS cohorts of European and East Asian ancestry and ethnicity specific meta-analyses, are freely available for download on the Kiryluk lab website: http://www.columbiamedicine.org/divisions/kiryluk/resources.php.

  Study phs001984

• A Phase I/IB Study of Ipilimumab or Nivolumab in Patients With Relapsed Hematologic Malignancies After Allogeneic Hematopoietic Cell Transplantation

  Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is characterized by poor outcomes and novel therapeutic options are urgently needed. Immune checkpoint blockade using CTLA-4 and PD-1 blocking antibodies are a potential concept for reinstating a dormant graft-versus-leukemia (GvL) effect.This study investigated transcriptomic changes in biopsies obtained from patients who received immune checkpoint blockade for relapsed hematologic malignancy post-HSCT and elucidated transcriptional programs associated with successful reinvigoration of GvL. Differential gene expression analysis showed evidence of increased T cell infiltration in biopsies of responders to ipilimumab treatment and demonstrated shared gene programs between GvL and GvHD.

  Study phs002377

• How are we funded?

  How are we funded? The EGA is provided infrastructure, administrative support, advisory input, and other relevant and necessary aspects by: CRG The EGA at the CRG is funded and supported by “La Caixa Foundation”, The Generalitat de Catalunya (Catalan Government), the Spanish Ministerio de Asuntos Económicos y Transformación Digital (Spanish Government) and the Instituto de Salud Carlos III. The Generalitat de Catalunya contributes with funding to the CRG and to the Barcelona Supercomputing Centre (BSC). The Barcelona Supercomputing Center is decisively contributing to EGA by providing the required compute, storage and networking resources, as well as key personnel for shared operations of EGA infrastructure. EMBL-EBI As part of the European Molecular Biology Laboratory (EMBL), the EGA at EMBL’s European Bioinformatics Institute receives funding from the governments of EMBL’s member states. The UK government, via UK Research and Innovation, also continues to support EMBL-EBI technical infrastructure, with EMBL supporting operational costs. A major source of funding for the EGA both at CRG and EMBL-EBI are competitive projects.The EGA resource continues to be funded through strategic engagement in collaborative partnerships and projects. Please see our projects page for more information. Other funders include the European Commission, the US National Institutes of Health, the Wellcome Trust, UK Research Councils, and our Industry Programme partners. Last updated on October, 2024.

  Documentation about/projects-and-funders/funders

• Sequencing Study in COPD cases and controls

  Since smokers with COPD have a higher risk of developing lung cancer than those without, we hypothesized that they carry more mutations in affected tissue. We called somatic mutations in airway brush samples from medium-coverage whole genome sequencing data from healthy never and ex-smokers (n=8), as well as from ex-smokers with variable degrees of COPD (n=4). Owing to the limited concordance of resulting calls between the applied tools we built a consensus, a strategy that was validated with high accuracy for cancer data.

  Study EGAS00001003406

• GBM-Space: Transcriptomic Profiling of Patient-Derived Glioblastoma Cell Lines (Parse Biosciences - Evercode WT)

  Cancer cells display heterogeneous and dynamic states in glioblastoma, but how these malignant states arise and whether they follow a tractable cellular trajectory across tumours is poorly understood. Here, we generate a deep single cell and spatial multi-region atlas of 12 isocitrate dehydrogenase wild-type (IDH-wt) primary glioblastomas that integrates transcriptomic, epigenomic and genomic analysis to comprehensively characterise their tumour heterogeneity. This dataset comprises sequencing data from single-cell transcriptomic profiles of patient-derived glioblastoma cell lines (Parse Biosciences Evercode WT v3), towards experimentally validating the malignant cell trajectory from developmental-like to gliosis-hypoxia states.

  Dataset EGAD00001016126

• Epidemiological study comparing rates and risk factors for dementia in African Americans in Indianapolis and Yoruba living in Ibadan, Nigeria

  In 1991 collaboration between researchers at Indiana University School of Medicine and the University of Ibadan, Ibadan, Nigeria established the Indianapolis-Ibadan Dementia Project. It is a longitudinal, prospective population-based comparative epidemiological study of the prevalence and incidence rates and risk factors of Alzheimer's disease and other age associated dementias. The project compares samples of community-dwelling elderly (age > 70 years) African Americans living in Indianapolis to Yoruba living in Ibadan, Nigeria, employing the same research design, methods, and investigators. It initially reported significantly lower prevalence rates of disorders in the Yoruba compared to the African Americans. In subsequent waves of the study (1994-1995, 1997-1998) incidence rates, rates of newly diagnosed cases, were also found to be significantly lower in the Yoruba. In genetic studies, the frequency of the APOE 4 allele was about the same in the two groups. APOE 4 was a significant risk factor for Alzheimer's disease and dementia in the Americans, while no association was found for the Yoruba. The APOE 2 allele appears to be protective in the Americans, but not the Yoruba. A constellation of factors often associated with vascular risk including a history of hypertension, diabetes, and high cholesterol levels is less common in the Yoruba than in the American group. An interaction was observed between cholesterol, APOE genotype and Alzheimer's disease in both study groups. In 2001-2002 survivors of the original cohort were once again evaluated (N~800 in each site) and 2,000 additional individuals age 70 years and older were enrolled in each site. Blood samples were collected from approximately 1,500 study participants in each site for genetic studies and analysis of biochemical risk factors for vascular disease. Subsequent waves of field work were conducted in 2004, 2007, 2009, and 2011. This fieldwork followed the classic two-stage study design. The study design involves an in-home screening interview with the study participant, which includes a cognitive assessment, medical history and current medications, brief neurological examination, height and weight, blood pressure measurement and assessment of social involvement. There is also a screening interview with a close relative of the study participant to assess activities of daily living, personality change, and medical history of the study participant. On the basis of the screening interview a sample of study participants (N~500 in each site) is selected for a full clinical diagnostic dementia work up which includes a neurological test battery, extensive interview with a family member and examination by a clinician. Diagnoses are made in a consensus diagnosis conference using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III R) and International Classification of Diseases 10th Revision (ICD-10) for dementia. The criteria of the National Institute for Neurological and Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association were used to diagnose possible and probable Alzheimer's disease. The focus of the study is risk factors for dementia and Alzheimer's disease, but also of particular importance is the question of mild cognitive impairment. This refers to the condition of having some decline in cognition but the decline is not sufficient to meet the criteria for dementia. We have studied this over the course of this project. In follow up studies of individuals who have this diagnosis about one third of them are better at follow up, about a third are about the same, and about a third decline more to meet the criteria for dementia. This is a very important issue for researchers because the ultimate goal of the research is to figure out how to identify the individuals who will definitely progress to dementia. If there are clear identifiers, it would be possible to make interventions, while individuals still function well, and possibly prevent the development of dementia altogether or delay the onset significantly. This is crucial because at the moment individuals usually do not enter into the medical care system until the dementia symptoms are quite severe, and the pathological damage to the brain cannot be undone.

  Study phs000378

• RNA004 DRS METTL5 variant

  RNA004 is a method for direct RNA sequencing (DRS) that holds promise to enhance the detection of modopathies. To this end, we provide DRS data for a patient sample harboring heterozygous inactivating SNPs for the methyltransferase METTL5, which modifies m6A on 18S rRNA. Companion datasets are 1) EGAS50000001201 for DRS of a healthy control with intact METTL5 and 2) PRJEB74238 for IVT 18S rRNA vector data as unmodified control.

  Study EGAS50000001321

• NHLBI TOPMed - NHGRI CCDG: Atherosclerosis Risk in Communities (ARIC)

  Participants from the Atherosclerosis Risk in Communities (ARIC) Study, a large population-based longitudinal cohort study, have been included in this Project and whole genome sequencing will be performed to contribute to analyses of early-onset atrial fibrillation and venous thromboembolism. Additional phenotype and genotype data are available for these individuals on dbGaP and can be accessed through the parent ARIC Cohort accession (phs000280). The National Heart, Lung and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program is designed to generate scientific resources to enhance understanding of fundamental biological processes that underlie heart, lung, blood and sleep disorders (HLBS). It is part of a broader Precision Medicine Initiative, which aims to provide disease treatments that are tailored to an individual's unique genes and environment. TOPMed will contribute to this initiative through the integration of whole genome sequencing (WGS) and other -omics (e.g., metabolic profiles, protein and RNA expression patterns) data with molecular, behavioral, imaging, environmental, and clinical data. In doing so, this program seeks to uncover factors that increase or decrease the risk of disease, identify subtypes of disease, and develop more targeted and personalized treatments. The Whole Genome Sequencing (WGS) Project is part of NHLBI's TOPMed program and serves as an initial step for the larger initiative.

  Study phs001211

• Longitudinal Studies of Patients with Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM)

  FPDMM (OMIM #601399) is a rare autosomal dominant disease characterized by defective megakaryocytic development, thrombocytopenia, platelet functional defects, and a life-long risk of developing hematological malignancies. FPDMM is caused by germline mutations in the RUNX1 gene, which encodes a master regulator of hematopoiesis. The overall lifetime risk of hematological malignancies in FPDMM patients is 35 - 45%. It is hypothesized that mutations in other genes cooperate with the germline RUNX1 mutations for leukemia development. However, it is not clear which genes need to be mutated for leukemia to develop and which biomarkers or clinical tests can be used to predict which patients will progress to leukemia. Likewise, there are no treatments and/or preventative measures that can reduce or stop disease progression except for stem cell transplantation, which is not available for all patients and may be associated with significant complications. To address these questions, we launched a longitudinal natural history study of patients associated with RUNX1 germline mutations at the NIH Clinical Center in early 2019 (Trial Registration ID: NCT03854318). The goals of this study are to: (1) perform comprehensive longitudinal phenotyping of FPDMM patients to document the full spectrum of both hematopoietic and non-hematopoietic manifestations of the disease; and (2) perform extensive genomic analyses of FPDMM patient samples to identify cooperating genomic variants, which may confer growth advantage that leads to clonal expansion of affected hematopoietic cells that may serve as the precursor to malignancies. The data available through dbGaP include exome sequencing and RNA-seq data from these patients. Diverse germline mutation types were identified in the RUNX1 gene, including splice site mutations and large deletions, in addition to nucleotide substitutions and small indels. Somatic mutations, especially in genes associated with clonal hematopoiesis of indeterminate potential (CHIP), were found in a substantial proportion of FPDMM patients who were leukemia-free. The findings suggest that the genomes in these patients are prone to somatic mutations and monitoring the dynamic changes of these somatic mutations prospectively may provide a way to predict progression to malignancies.

  Study phs003075

• Genome-wide mutational consequences of nucleotide excision repair-deficiency through XPC deletion in a human adult stem cell culture

  Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Deficiency in this pathway can contribute to the development of cancer and accelerate aging. NER-deficiency is an important determinant for cancer treatment outcome, as NER-deficient tumors are selectively sensitive to cisplatin treatment. While NER-deficiency has been linked to mutational Signature 5, not all NER-deficient tumors are characterized by a high Signature 5 contribution, illustrating the importance to further characterize the mutational consequences of NER-deficiency. Here, we analyzed the mutational profile of a human adult stem cell (organoid) culture that is deficient in NER through XPC deletion by CRISPR-Cas9 gene-editing, and subsequent whole-genome sequencing analysis of a clonally derived organoid. We found that XPC deletion results in an increase in base substitution load and specifically induces Signature 8 mutations, a mutational signature with previously unknown etiology. Presence of Signature 8 may, therefore, serve as a novel biomarker for NER-deficient tumors and could improve personalized treatment strategies.

  Study EGAS00001002681

• eMERGE: Northwestern (NUgene) WGS

  The NUgene Project is a biorepository with longitudinal medical information from participating patients at Northwestern Medicine affiliated hospitals and outpatient clinics. Participants' DNA samples are coupled with data from a self-reported questionnaire (2 versions were used, 1 before and 1 after February 2006, both are included) and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 3 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated enterprise data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators. The electronic MedicalRecords and Genomics (eMERGE) Network is a consortium of 9 clinical sites with EMR linked DNA biobanks, including Northwestern University and its NUgene biobank, funded by the NHGRI (National Human Genome Research Institute) to investigate the use of electronic medical record systems for genomic research. The goal of eMERGE is to conduct genome-wide association studies in approximately 100,000 individuals using EMR-derived phenotypes and DNA from linked biorepositories. Using electronic phenotyping methods, the consortium has been and is using DNA samples from all participating sites to explore the genetic determinants of approximately 80 phenotypes, including both diseases and traits, for which the electronic phenotyping algorithms have or are being published on PheKB.org. Thus, for the eMERGE network, ~900 NUgene subjects were selected, as described in the study inclusion/exclusion criteria section below, to be genotyped using whole genome sequencing (WGS), for use in the eMERGE network as eMERGE subjects. The criteria used below were selected so that these subjects will likely meet the criteria to be cases and/or controls, of diverse races and/or ethnicities, for at least 1 of the ~80 phenotypes being studied within eMERGE, and could be recontacted for future research if needed.

  Study phs001191

• Whole-genome sequencing of two probands with hereditary spastic paraplegia reveals novel splice-donor region mutation and known pathogenic mutation in SPG11

  Hereditary spastic paraplegias (SPG) are a group of heterogeneous neurodegenerative disorders, which are often presented with overlapping phenotypes such as progressive paraparesis and spasticity. To assist the diagnosis of SPG subtypes, next-generation sequencing is often used to provide supporting evidence. In this study, we report the case of two probands from the same family with SPG symptoms, including bilateral lower limbs weakness, unsteady gait, cognitive decline, dysarthria and slurring of speech since age of 14. Subsequent whole-genome sequencing revealed that the patients are compound heterozygous for mutations in SPG11 gene, including the paternally inherited c.6856C>T (p.Arg2286*) mutation and the novel maternally inherited c.2316+5G>A splice donor region mutation. Mutations in SPG11 are the common cause of autosomal recessive Spastic Paraplegia type 11. According to the ClinVar database, there are already 101 reported pathogenic mutations in SPG11 that are associated with SPG. To our knowledge, this is the first report of SPG11 mutations in our local population. Novel splice mutation identified in this study would enrich the catalog of SPG11 mutations, potentially leading to better genetic diagnosis of SPG.

  Study EGAS00001001849

• Genomic profiling of Follicular thyroid adenomas and carcinomas using exome-sequencing analyses

  While thyroid nodules per se are frequent (4%–50%), thyroid cancer is rare (∼5% of all thyroid nodules). The minimally invasive Fine Needle Aspiration Cytology (FNAC) is the current gold standard for the diagnosis thyroid nodule malignancy. However, proper discrimination of follicular neoplasias often require more invasive diagnostic techniques. To develop a novel molecular classification system for thyroid cancer malignancy, we performed an genomic profiling of 54 fresh frozen Follicular like thyroid samples using a whole exome sequencing approach (SureSelect V6 Target enrichment protocol and the Illumina Novaseq 6000 platform)

  Study EGAS00001005561

• Targeted pancancer RNA-Seq

  This dataset contains targeted RNA-Seq generated with the Illumina RNA Pan-Cancer panel. It comprises 2200 cancers from children and adults. The cancers represent a wide range of CNS, solid and haematopoeitic tumours. Samples are from pathology specimens including FFPE, fresh frozen, bone marrow aspirate and peripheral blood.The data is used for tumour driver identification. SNVs, indels and fusion detection.

  Study EGAS50000000700

• single cell RNA-seq of peripheral blood from analysis in infants with MLL-rearranged Acute Lymphoblastic Leukemia

  This dataset contains two experiments. 1) Single cell RNA-seq of peripheral blood diagnostic samples from patients with MLL-rearranged infant ALL that underwent relapse or not (samples ending in R relapsed, samples ending in N did not), sequenced with SORT-seq (see cell systems, 2016, doi:10.1016/j.cels.2016.09.002). For some of the patients, multiple indipendent plates were produced (each plate is a sample). Barcode-well correspondence can be found here: https://bitbucket.org/princessmaximacenter/sharq/src/master/data/celseq2_bc384-v4.csv . 2) Single cell RNA-seq of peripheral blood diagnostic samples from patients with MLL-rearranged infant ALL that underwent relapse or not (samples ending in R relapsed, samples ending in N did not), sequenced with10x Genomics Version 2.

  Dataset EGAD00001007752

• Chromatin accessibility in human monocyte differentiation

  This dataset consists of ATAC-seq data from human monocytes, monocyte-derived dendritic cells or monocyte-derived macrophages as well as monocyte-derived cells that were subjected to siRNA treatment targeting TET2, IRF4 and EGR2. In total, it includes 26 samples.

  Dataset EGAD00001006601

• Comprehensive molecular profiling for breast cancer patients and high-risk individuals.

  Although germ-line mutations in BRCA1 and BRCA2 gene are responsible for familial breast and ovarian cancer, the detailed mechanism of tumorigenesis is yet unknown. Here, we performed next-generation sequencing to determine the genomic profiles of familial breast cancer tumorigenesis. Target-capture sequencing of fresh-frozen or formalin-fixed-paraffin-embedded (FFPE) samples of breast cancer or normal breast tissue were performed.

  Study JGAS000368

• Targeted Myeloid DNA-Panelsequencing, MLL

  Sequencing data from a targeted myeloid DNA-Panelsequnencing at the MLL Dx, Munich lab. Targeted sequencing was performed using the Nextera DNA Flex library preparation kit, starting with 100ng of genomic DNA (Illumina, San Diego, CA, USA). The target regions were enriched by a custom xGen Lockdown panel using a hybridization capture workflow (IDT Integrated DNA Technologies, Coralville, IA, USA). All libraries were sequenced with 100bp paired-end reads on a NovaSeq6000 (Illumina) with a mean coverage of 3206x. Somatic variant calling was performed with Pisces and a sensitivity cut off of 2%. Large deletions and medium-sized insertions, as they are for example found in CALR and FLT3, were called with Pindel. Variant annotation considered the publicly available data bases Cosmic (v91), ClinVar (2020-03), gnomAd (non-cancer, v2.1.1), dbNSFP (v3.5) and UMD TP53 (2017_R2). Variants that are described as somatic, protein truncating or affecting splice sites were considered as mutations while variants with no or discrepant data base information were considered as variant of uncertain significance.

  Dataset EGAD00001008485

• Population Architecture using Genomics and Epidemiology (PAGE): Multiethnic Cohort (MEC)

  The Multiethnic Cohort (MEC) has established a large biorepository of blood and urine (N=67,000) and cryopreserved lymphocytes (N=15,000) linked to extensive, prospectively collected risk factors (e.g., diet, smoking, physical activity), biomarkers and clinical data for five racial/ethnic groups. This cohort study of over 215,000 men and women in Hawaii and California is unique in that it is population-based and includes large representations of older adults (45-75 yrs at baseline) for five US racial/ethnic groups (Japanese Americans, African Americans, European Americans, Latinos and Native Hawaiians) at varying risks of chronic diseases. Within the PAGE investigation, the MEC proposes to study: 1) diseases for which we have DNA available for large numbers of cases and controls (breast, prostate, and colorectal cancer, diabetes, and obesity); 2) important cancers that are less common (e.g., lung, pancreas, endometrial cancers, NHL) but for which we propose to pool our data with other funded groups; 3) common traits that are risk factors for these diseases (e.g., body mass index/weight, waist-to-hip ratio, height) and 4) relevant disease-associated biomarkers (e.g., fasting insulin and lipids, steroid hormones). The specific aims are: 1) To determine the population-based epidemiologic profile (allele frequency, main effect, heterogeneity by disease characteristics) of putative causal variants in the five racial/ethnic groups in the MEC; 2) for variants displaying effect heterogeneity across ethnic/racial groups, we will utilize differences in LD to identify a more complete spectrum of associated variants at these loci; 3) investigate gene x gene and gene x environment interactions to identify modifiers; 4) examine the associations of putative causal variants with already measured intermediate phenotypes (e.g., plasma insulin, lipids, steroid hormones); and 5) for variants that do not fall within known genes, start to investigate their relationships with gene expression and epigenetic patterns in small genomic studies. This study is part of the Population Architecture using Genomics and Epidemiology (PAGE) study phs000356.

  Study phs000220

• Center for Craniofacial and Dental Genetics (CCDG): Genetics of Orofacial Clefts and Related Phenotypes

  The purpose of this study is to investigate the genetics of orofacial clefts (OFCs) in a large study population, and importantly, to incorporate subclinical phenotypic features into these studies. Orofacial clefts (OFCs) comprise a significant fraction of human birth defects (about 1/700 live births (Rahimov et al. 2012) and represent a major public health challenge, as individuals with these anomalies require surgical, nutritional, dental, speech, medical and behavioral interventions, thus imposing a substantial economic and personal burden (Berk and Marazita 2002*). The most common forms include OFCs of the lip alone (CL, Figure 1A), CL plus cleft palate (CL+CP, Figure 1B) or of the palate only (CP, Figure 1C). Individuals born with OFC may have their first surgical repair at age 3 months, but this initial surgery is just the beginning of a lifetime of health burdens. An individual born with an OFC has a hospital use rate increased for most ages (up to 233% increase for children ages 0-10 years and 16% for middle aged adults (Wehby et al. 2012). Healthcare costs for children with OFCs are estimated to be 800% greater compared with their unaffected peers (Boulet et al. 2009). Data from Denmark show that people born with CL with or without CP (CL/P) have an increased mortality up to age 55, which may be attributed to an increased risk of suicide and/or certain cancers (Christensen et al. 2004). The focus of most OFC genetic research has been CL and/or CP. Furthermore, the majority of OFC, i.e. about 70% of CL/P and 50% of CP is considered "nonsyndromic" (Jones 1988), i.e. isolated anomalies with no other apparent cognitive or structural abnormalities. Figure 1 Sample OFC Types A: Bilateral Cleft Lip; B:Cleft Lip plus Cleft Palate; C:Cleft Palate Alone The factors leading to the majority of nonsyndromic OFCs are still unclear, particularly at an individual family level. As is true for many complex traits, substantial progress in gene identification has occurred in the OFC field in the last two years (Dixon et al. 2011; Marazita 2012). Genome Wide Association Studies (GWAS) and sequencing studies to date by our research team and others have focused on genetic risk factors for overt CL/P and CPO-and have been very successful. A major finding from this work is that OFCs exhibit significant genetic heterogeneity, i.e., multiple genetic regions have been implicated (Beaty et al. 2010; Ludwig et al. 2012). Thus, approaches are needed to understand this genetic heterogeneity. Are there GxG interactions at work? Are there subsets of families, each due to a different gene? Our research group has shown that a promising approach to dissect the etiology of OFC is to focus on subclinical phenotypic features within entire cleft families (not just in affected cases, but also in their non-cleft relatives). These subtle features are believed to represent mild manifestations of the same underlying genetic susceptibility responsible for OFCs; as such, their inclusion in case-control and family-based genetic studies can help to clarify and refine the relationship between genotype and phenotype. The study population comprises a large number of families and individuals (~12,000 individuals) from multiple populations worldwide (Caucasians from the US and Europe, Asians from China and the Philippines, Mixed Native American/Caucasians from South America, and Africans from Nigeria and Ethiopia). There are cases, case families (nuclear families and extended kindreds), as well as controls with no history of OFC nor other developmental defects. *Berk NW, Marazita ML (2002) Costs of Cleft lip and Palate: Personal and Societal Implications. In: Wyszynski DF (ed) Cleft Lip and Palate: From Origin to Treatment. Oxford University Press, Inc., New York, pp 458-467.

  Study phs000774

• Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy

  Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits including cardiovascular diseases.Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 149 (97)* patients with dilated cardiomyopathy and 113 (108)* non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage and allele specific expression. Systematic annotation of genome wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome wide association signals in two independent cohorts.Conclusions: RNA transcription, splicing and allele specific expression are each important determinants of the DCM phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics. (*) numbers in parentheses represent samples that the publication is based on.

  Study EGAS00001002454

• The ClinSeq Project: Piloting Large-Scale Genome Sequencing for Research in Genomic Medicine

  ClinSeq is a pilot project to investigate the use of whole-genome sequencing as a tool for clinical research. By piloting the acquisition of large amounts of DNA sequence data from individual human subjects, we are fostering the development of hypothesis-generating approaches for performing research in genomic medicine, including the exploration of issues related to the genetic architecture of disease, implementation of genomic technology, informed consent, disclosure of genetic information, and archiving, analyzing, and displaying sequence data. In the initial phase of ClinSeq, we are enrolling roughly 1000 participants; the evaluation of each includes obtaining a detailed family and medical history, as well as a clinical evaluation. The participants are being consented broadly for research on many traits and for whole-genome sequencing. Initially, Sanger-based sequencing of 300-400 genes thought to be relevant to atherosclerosis is being performed, with the resulting data analyzed for rare, high-penetrance variants associated with specific clinical traits. The participants are also being consented to allow the contact of family members for additional studies of sequence variants to explore their potential association with specific phenotypes. Here, we present the general considerations in designing ClinSeq, preliminary results based on the generation of an initial 826 Mb of sequence data, the findings for several genes that serve as positive controls for the project, and our views about the potential implications of ClinSeq. The early experiences with ClinSeq illustrate how large-scale medical sequencing can be a practical, productive, and critical component of research in genomic medicine. Reprinted from Genome Res. 2009 Sep; 19(9): 1665-1674, with permission from Genome Research, PMID: 19602640.

  Study phs000971

• Genetic Study of Vascular Anomalies

  Vascular anomalies are malformations or tumors of the vasculature that can result in significant morbidity and mortality. Vascular anomalies are caused by germline or post-zygotic pathogenic variants in genes that regulate cell growth and vascular development. Complex or extensive vascular anomalies are often intractable despite interventions such as sclerotherapy, embolization, or surgery. In recent years, targeted therapy has played an increasingly crucial role in the management of these diseases. Identification of the molecular causes of vascular anomalies is essential to provide efficacious therapy; however, genetic profiling is often limited by difficulty obtaining affected tissues and limited sequencing depth. The lack of this information limits treatment options and the precision of targeted therapy, especially for primary complex lymphatic anomalies. To address these limitations, we have applied novel techniques, including analysis of unconventional samples such as endothelial cells isolated from lymphatic fluid and cell-free DNA, deep coverage exome sequencing, and unique molecular identifier ultra-deep targeted sequencing, in the molecular profiling of these diseases.

  Study phs003197

• NINDS-Genome-Wide Genotyping in Parkinson's Disease: First Stage Analysis and Public Release of Data

  Epidemiological studies have estimated a cumulative prevalence of PD of greater than 1 per thousand. When prevalence is limited to senior populations, this proportion increases nearly 10-fold. The estimated genetic risk ratio for PD is approximately 1.7 (70% increased risk for PD if a sibling has PD) for all ages, and increases over 7-fold for those under age 66 years. The role for genes contributing to the risk of PD is therefore significant. This study utilized the well characterized collection of North American Caucasians with Parkinson's disease, and neurologically normal controls from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection for a first stage whole genome analysis. Genome-wide, single nucleotide polymorphism (SNP) genotyping of these publicly available samples was originally done in 267 Parkinson's disease patients and 270 controls, and this has been extended to include genome wide genotyping in 939 Parkinson's disease cases and 802 controls. The NINDS repository was established in 10-2001 towards the goal of developing standardized, broadly useful diagnostic and other clinical data and a collection of DNA and cell line samples to further advances in gene discovery of neurological disorders. All samples, phenotypic, and genotypic data are available to the research community including to academics and industry scientists. In addition, well characterized neurologically normal control subjects are a part of the collection. This collection formed the basis of this first stage study by Fung et al., and the expanded study by Simon-Sanchez et al. The genotyping data was generated and provided by the laboratory of Dr. Andrew Singleton NIA, and Dr. John Hardy NIA (NIH Intramural, funding from NIA and NINDS). Important links to apply for individual-level data Data Use Certification Requirements (DUC) Apply here for controlled access to individual level data Participant Protection Policy FAQ

  Study phs000089

• Multiple esclerosis and mixed microbial infections

  This Project deals with the sequencing of ITS1 region, which is highly variable both in length and in nucleotide sequence for different yeast using yeast-specific primers ITS1 and ITS2. A total of 19 samples involving different brain regions from patients with different conditions were analysed. Of these, 10 are controls-healthy patients and 9 multiple sclerosis (MS) patients.

  Study EGAS00001002957

• Dataset_for_linked_WES_and_WGS_data_from_EGAS00001004813 which belong also to EGAS00001005537 for germline controls of rare cancers

  WES/WGS sequencing data of 37 germline runs, which were uploaded to umbrella studies. The sequencing was always paired. The WGS sequencing was on HiSeq X Ten using the Illumina TruSeq DNA Nano Kit. The WES Sequencing was on HiSeq4000 with Agilent Sureselect V5+UTR.

  Dataset EGAD00001010046

• Dataset for upper_gastrointestinal_tumor-WHOLE_GENOME

  Rare cancer sequencing data of 28 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008901

• DAC for Combined MEK and BCL-2/XL inhibition is effective in high-grade serous ovarian cancer patient-derived xenograft models and BIM levels are predictive of responsiveness

  Dac EGAC00001001250

• RNA stability controlled by m6A methylation contributes to X-to-autosome dosage compensation in mammals

  In mammals, X-chromosomal genes are expressed from a single copy since males (XY) possess a single X chromosome, while females (XX) undergo X inactivation. To compensate for this reduction in dosage compared to two active copies of autosomes, it has been proposed that genes from the active X chromosome exhibit dosage compensation. However, the existence and mechanism of X-to-autosome dosage compensation are still under debate. Here, we show that X-chromosomal transcripts are reduced in m6A modifications and more stable compared to their autosomal counterparts. Acute depletion of m6A selectively stabilises autosomal transcripts, resulting in perturbed dosage compensation in mouse embryonic stem cells. We propose that higher stability of X-chromosomal transcripts is directed by lower levels of m6A, indicating that mammalian dosage compensation is partly regulated by epitranscriptomic RNA modifications.

  Study EGAS00001007112

• A brain precursor atlas reveals the acquisition of developmental-like states in adult cerebral tumours

  We generated a single-cell RNA-seq atlas capturing over 100,000 cells spanning all stages of the mouse cerebral development. By examining data from over 100 cerebral tumour samples, our study reveals that, despite the phenotypic/genotypic differences between the tumour types, they are all comprised of developmental sublineages that map most closely to embryonic or juvenile stages of development.

  Dataset EGAD00001008746

• Single-Cell Genomic and Transcriptomic Analysis of the Aging Human Brain

  We studied human brain aging using single-cell whole genome sequencing and single-nucleus RNA sequencing of the pre-frontal cortex from 19 donors ranging in age from 0.4 years to 104 years. All donors were free of neuropathology and none received a clinical neurological diagnosis prior to death. snRNA-seq libraries were prepared in batches that always included old and young donors to mitigate batch effects in the preparations. Neurons for single-cell WGS were collected from the same tissue region as the snRNA-seq for each donor but represent independent cells. Multiplexed error-robust fluorescent in-situ hybridization (MERFISH) data was also collected from pre-frontal cortex samples of a subset of the 19 donors. Transcriptomic results identified infant-specific cell clusters, and common-down regulation of cell-essential genes involved in ribosomes, transport, homeostasis and metabolism during aging, across all cell types. scWGS identified two-age associated mutational signatures, as well as gene-length and expression-level dependent somatic mutation rates in neurons. Raw sequencing data in fastq format for single-nucleus RNA-seq and single-cell DNA-seq, as well as cell and gene count matrix, transcript metadata, and cell metadata for MERFISH will be available in dbGaP.

  Study phs003445

• exploration of biomarkers discriminating squamous cell carcinoma from other lung cancers

  Targeted therapies based on the molecular and histological features of cancer types are becoming standard practice. The most effective regimen in lung cancers is different between squamous cell carcinoma (SCC) and adenocarcinoma (AD). Therefore a precise diagnosis is crucial, but this has been difficult, particularly for poorly differentiated SCC (PDSCC) and AD without a lepidic growth component (non-lepidic AD). Biomarkers enabling a precise diagnosis are therefore urgently needed. To achieve this goal, we initially performed CAGE (Cap Analysis of Gene Expression) to quantify promoter activities on 97 frozen tissues from surgically resected lung cancers (22 SCC and 75 AD). We furhter expanded the transcriptome profiling to cover additional 48 malignant neoplasm of bronchus and lung, including mesothelioma and metastatic lung cancers derived from other tissues.

  Study JGAS000488

• Diet, Genetic Factors, and the Gut Microbiome in Crohn's Disease

  We investigate the hypothesis that consistent changes in the human gut microbiome are associated with Crohn's disease, a form of inflammatory bowel disease, and that altered microbiota contributes to pathogenesis. Analysis of this problem is greatly complicated by the fact that multiple factors influence the composition of the gut microbiota, including diet, host genotype, and disease state. For example, data from us and others document a drastic impact of diet on the composition of the gut microbiome. No amount of sequencing will yield a useful picture of the role of the microbiota in disease if samples are confounded with uncontrolled variables. We aim to characterize the composition of the gut microbiome while controlling for diet, host genotype, and disease state. Diet is controlled by analyzing children treated for Crohn's disease by placing them on a standardized elemental diet, and by testing effects of different diets on the gut microbiome composition in adult volunteers. Genotype is analyzed by large scale SNP genotyping, which is already underway and separately funded--team member Hakon Hakonarson is currently genotyping 50 children a week at ~half a million loci each and investigating connections with inflammatory bowel disease. Clinical status is ascertained in the very large IBD practice in the UPenn/CHOP hospital system. Effects of diet, host genotype, and disease state on the gut microbiome are summarized in a multivariate model, allowing connections between microbiome and disease to be assessed free of confounding factors. This project is divided into four sub-studies. In the Fecal Storage Methods (FSM) study, methods of stool storage and DNA extraction are compared to examine their impact on DNA sequence analysis results. The Controlled Feeding Experiment (CaFE) addresses the effects of controlled diets on the gut microbiome. In the Cross-sectional Study of Diet and Stool Microbiome Composition (COMBO), the effects of diet analyzed using surveys and deep sequencing of stool specimens. The fourth study, Pediatric Longitudinal Study of Elemental Diet and Stool Microbiome Composition (PLEASE), examines the effects of an elemental diet treatment on pediatric patients diagnosed with inflammatory bowel disease (IBD), particularly Crohn's disease. Fecal Storage Methods (FSM): Cross-sectional study Controlled Feeding Experiment (CaFE): Controlled trial Cross-sectional Study of Diet and Stool Microbiome Composition (COMBO): Cross-sectional study Pediatric Longitudinal Study of Elemental Diet and Stool Microbiome Composition (PLEASE): Longitudinal cohort study

  Study phs000252

• Error-corrected sequencing of 26 driver genes (additional cohort)

  An additional 320 swab samples were sequenced. The bam files contain consensus reads.

  Dataset EGAD50000000641

• A Combined Omics and Tissue Biobank for Paediatric Cancers

  The Swedish Childhood Tumour Biobank (BTB) is a nonprofit national infrastructure for samples and genomic data collection from pediatric patients diagnosed with central nervous system and other solid tumours in Sweden. Fresh frozen tumour tissue and patient’s matched blood are collected from affected patients and genomic data is continuously generated and made available for approved medical research projects. We expect that the accessibility of biological samples and/or data to the research community will contribute to further advances in the understanding of tumour biology, which in turn will impact many aspects of clinical care of children with cancer, by refining diagnosis and/or identifying oncogenic drivers and therapeutic targets.

  Study EGAS50000000209

• DCIS fresh frozen fragmentomics dataset

  Ductal carcinoma in situ (DCIS) is a non-obligate precursor lesion of breast cancer (BC). Often detected by mammography, most cases are managed through surgical and/or radiotherapy approaches. Today, it is not possible to predict which patients will progress to invasive disease. Here, we evaluated high-depth whole-genome sequenced (WGS) DCIS, enriched for highgrade clinical lesions, to understand whether deep WGS could reveal biological insights and/or personalized therapeutic vulnerabilities that may be targetable. We find genomic locations that are likely susceptible to producing the initiating lesion for structural variations (SVs) prone to subsequent evolution, termed SHOREs (Susceptibility HOtspots for Rearrangements and ongoing Evolution). We additionally highlight individualized therapeutic potential that would otherwise not be appreciable without WGS. We posit that holistic WGS profiling could offer a more precise stratification approach, discerning higher-risk cases for prospective clinical studies on personalized therapies, from truly low-risk cases suitable for active monitoring. To substantiate our WGS findings, we also performed RNAseq on the same samples, this EGA study contains the RNAseq data.

  Study EGAS50000001475

• Identification of a Fumarate-Hydratase Deficient-like RCC Subtype with Convergent Pathway Alterations

  The development of molecularly targeted therapies builds upon the identification of tumor clades with shared molecular abnormalities. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a familial syndrome resulting from germline mutation of the two-hit tumor suppressor gene, Fumarate Hydratase (FH). HLRCC renal tumors present often in young adults, exhibit unique histological features and are particularly aggressive. HLRCC is uncommon and poorly understood, and whether there are sporadic renal tumors with similar characteristics, is unclear. Notably, FH can also be inactivated somatically in RCC, and should be included among FH-deficient (FHD) kidney tumors. We identified a tumor clade without FH mutations but with similar morphological and molecular characteristics as well as aggressive clinical behavior, which we name FHDL (FHD-like). We show that FHD/FHDL tumors represent a unique subtype of CIMP (CpG Island Methylator Phenotype) with the highest levels of overall genome methylation and CDKN2A silencing. FHD/FHDL tumors are characterized by convergent activation of the Hippo pathway as determined by frequent and mutually exclusive mutations in NF2 and PTPN14. AKR1B10, an NRF2 target, was upregulated in FHD/FHDL tumors as well as GATA3, which suggests a shared origin in the renal medulla and is consistent with topological studies. There is loss of 5-hydroxymethylcytosine in both FHD and FHDL tumors. These data define a group of particularly aggressive renal cancers with shared molecular features and potential targets for therapeutic intervention.

  Study EGAS00001002646

• Genome-Wide Approach to Measure Variant-Based Heritability of Drug Outcome Phenotypes

  Current pharmacogenetic approaches often use a few large-effect alleles to predict drug outcomes. However, many drug outcome phenotypes are determined by complex pathways that may be influenced by common single-nucleotide variants (SNVs) across the genome. We ascertained how much variation in drug response is explained by common SNVs for pharmacokinetic (drug levels) and pharmacodynamic phenotypes (highest creatinine) for 4 drugs: vancomycin, gentamicin, cyclosporine and tacrolimus.

  Study phs002506

• The malaria-protective human glycophorin structural variant DUP4 shows somatic mosaicism and association with hemoglobin levels

  Glycophorin A and glycophorin B are red blood cell surface proteins that are both receptors for the parasite Plasmodium falciparum, which is the principal cause of malaria in sub-Saharan Africa. DUP4 is a complex structural genomic variant that carries extra copies of a glycophorin A - glycophorin B fusion gene, and has a dramatic effect on malaria risk by reducing the risk of severe malaria by up to 40% Using fiber-FISH and Illumina sequencing, we validate the structural arrangement of the glycophorin locus in the DUP4 variant, and reveal somatic variation in copy number of the glycophorin A- glycophorin B fusion gene. By developing a simple, specific, PCR-based assay for DUP4 we show the DUP4 variant reaches a frequency of 13% in a malaria-endemic village in south-eastern Tanzania. We genotype a substantial proportion of that village and demonstrate an association of DUP4 genotype with hemoglobin levels, a phenotype related to malaria, using a family-based association test. Taken together, we show that DUP4 is a complex structural variant that may be susceptible to somatic variation, and show that it is associated with a malarial-related phenotype in a non-hospitalizedlongitudinally-followed population.

  Study EGAS00001003239

• Molecular Etiology of Early-Onset Dystonia

  Primary torsin dystonias (PTD) are a group of movement disorders characterized by twisting muscle contractures, where dystonia is the only clinical sign (except for tremor) and there is no evidence of neuronal degeneration or an acquired cause. Eleven genes have been mapped for primary dystonia including DYT1 (TOR1A), DYT2, DYT4 (TUBB4A), DYT6 (THAP1), DYT7, DYT13,, DYT17, DYT21, CIZ1, DYT24 (ANO3), and DYT25 (GNAL); however, only 3 genes (TOR1A, THAP1, and GNAL) have mutations in early onset dystonia patients. Each is inherited as an autosomal dominant trait but with reduced penetrance, meaning that individuals can carry the mutation but do not show clinical symptoms. The most common form of PTD is adult onset focal accounting for about 90% of all cases of dystonia with a prevalence estimated at 30/100,000 in the general population. A small percentage of focal cases are due to mutations in CIZ1, ANO3, THAP1, TUBB4A, and GNAL, but the vast majority is unaccounted for and is most likely multigenic or multifactorial. In this grant, focusing on early onset PTD, we will uncover genes that influence the penetrance of DYT1 (TOR1A) dystonia through GWAS and exome sequencing studies. We will identify other genes for early onset PTD using exome sequencing and determine whether variants within the identified early onset PTD genes or the pathways associated with these genes contribute to susceptibility in the most prevalent form of PTD, focal dystonia, using a case:control association study. The proposed research will identify novel PTD risk factors and genes, which in turn should reveal shared and intersecting pathways leading to a better understanding of the molecular basis of PTD and provide the underpinnings for developing new treatments. Additionally, insight into the factors that modulate disease penetrance would be a first step in determine whether these could be modified leading to a reduced incidence of the disease.

  Study phs001733

• scRNASeq of human innate lymphoid cells from different compartments

  Group 1 innate lymphoid cells (ILCs) comprise a heterogeneous family of cytotoxic natural killer (NK) cells and ILC1s. We identifiy a population of “liver-type” ILC1s with transcriptional, phenotypic, and functional features distinct from those of conventional and liver-resident NK cells as well as from other previously described human ILC1 subsets. LT-ILC1s were CD49a+CD94+CD200R1+, expressed the transcription factor T-BET, do not express the activating receptor NKp80, or the transcription factor EOMES. Similar to NK cells, liver-type ILC1s produce IFN-γ, TNF-α, and GM-CSF; however, liver-type ILC1s also produce IL-2 and lack perforin and granzyme B. Liver- type ILC1s are expanded in cirrhotic liver tissues, and they can be produced from blood-derived ILC precursors in vitro in the presence of TGF-β1 and liver sinusoidal endothelial cells. Cells with similar signature and function can also be found in tonsil and intestinal tissues. Collectively, our study identifies and classifies a population of human cross-tissue ILC1s.

  Study EGAS00001006847

• Transcriptome analysis of Williams syndrome

  Williams syndrome (WS) is a neurodevelopmental disorder caused by microdeletion on chromosome 7q11.23, and has attracted much attention for its distinctive features, such as hypersociability. However, it remains unclear which genes are involved in the complex phenotypes of their condition. Here, we performed transcriptome analysis of peripheral blood to identify genes associated with WS.

  Study JGAS000132