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• Whole genomes sequencing BAM files (blood and lung brushings) of COPD cases and controls (EvA)

  Dataset of 27 whole genome sequencing files (BAM), which cover 12 individuals out of which four suffer from COPD. From 9 individuals, there are sequencing data from blood and from lung brushings at one single site available, from another 3 there is additionally a lung brushing sequencing file from a second site available. Comparison of blood with lung brushings allows the calling of somatic mutations within a tissue.

  Dataset EGAD00001004535

• Joslin Study on the Genetics of Type 2 Diabetes

  Between 1993 and 2003, families were recruited in the Joslin Study on the Genetics of Type 2 Diabetes for the presence of an autosomal dominant mode of inheritance of diabetes. Recruiting and screening of families occurred through probands who were receiving medical care at the Joslin Clinic (Boston, MA). Screening of families included 1) a proband and at least one sibling with type 2 diabetes, 2) diabetes occurring in at least three generations, 3) diabetes inherited on one side of the prospective family. Probands had to have a diabetes diagnosis between the age range from 10 to 60 years. Demographic data, clinical data, and family history were collected from participating family members, along with blood and urine samples. This study includes genetic and phenotypic data from one family examined in Simeone, Wilkerson, et. al. (NPJ Genomic Medicine 2022, PMID: 35869090). Genotype data for 14 family members and whole genome sequencing data for 6 individuals were generated with the goal of identifying a potential genetic cause of disease in this family. To de-identify this family and protect confidentiality, information on sex in phenotype data and variants identified in X, Y, and MT chromosomes have been removed in compliance with IRB guidelines.

  Study phs002959

• Glioblastoma CRISPR Screen (2017-04-27)

  This is an in vitro genome-wide CRISPR/cas9 screen in human glioblastoma stem cells, screening for genes essential for survival of these cells. These cells express cas9 and have been transfected with a guide RNA library causing gene knockouts. We will analyse the sequencing data for depletion of guide RNAs. This dataset contains all the data available for this study on 2017-04-27.

  Dataset EGAD00001003308

• Glioblastoma CRISPR Screen (2016-06-02)

  This is an in vitro genome-wide CRISPR/cas9 screen in human glioblastoma stem cells, screening for genes essential for survival of these cells. These cells express cas9 and have been transfected with a guide RNA library causing gene knockouts. We will analyse the sequencing data for depletion of guide RNAs. This dataset contains all the data available for this study on 2016-06-02.

  Dataset EGAD00001002158

• Genetic Investigations of Attention-Deficit/Hyperactivity Disorder

  Design and Aims:We conducted whole-exome DNA sequencing on 152 parent-child trios (456 individuals total) that included a child meeting DSM-IV or DSM-5 criteria for ADHD along with both biological parents to identify rare de novo damaging DNA variants associated with ADHD risk. Mutation rates were compared between 147 ADHD trios and 780 unaffected control trios. We aimed to identify specific ADHD risk genes by combining the de novo trio data with rare variant data from an independent case-control cohort.Population Information:ADHD trios were collected from four sites. The 780 control trios were unaffected siblings from the Simons Simplex Collection who scored in the normal range on the Child Behavior Checklist (CBCL) or Adult Behavior Checklist (ABCL) ADHD subscale.Molecular Technologies:Whole-exome DNA sequencing was performed on the ADHD trios using the IDT xGen V1 or Agilent SureSelect All Exon V7 capture and the Illumina NovaSeq6000 sequencer. Control trios were previously sequenced with the NimbleGen SeqCap EzExomeV2 capture and Illumina HiSeq 2000 sequencer. Joint variant calling was performed for all trios. Rare de novo variants with allele frequency Principal Findings:We found a 1.67-fold enrichment of rare de novo damaging variants and a 1.93-fold enrichment of ultra-rare de novo damaging variants in ADHD cases vs controls. By integrating the de novo data with an independent case-control cohort, KDM5B was identified as a high-confidence ADHD risk gene (FDR=0.04). Three potential risk genes were also identified. Twenty-three genes with ultra-rare damaging de novo variants in ADHD overlapped with previously reported risk genes for other neuropsychiatric conditions. Exploratory analyses showed enrichment of these genes in early neurodevelopmental pathways.

  Study phs003647

• STAMPEED: Northern Finland Birth Cohort 1966 (NFBC1966)

  The Northern Finland Birth Cohorts program (NFBC) was initiated in the 1960s in the two northernmost provinces of Finland to study risk factors involved in pre-term birth and intrauterine growth retardation, and the consequences of these early adverse events on subsequent morbidity and mortality. The uniqueness of NBFCs is that the data of the cohorts were obtained from early fetal life (including maternal health during pregnancy) to adulthood. The NFBC1966 includes 12,058 live births to mothers in the two northern-most provinces of Finland. Two decades later, a second cohort of 9432 births was obtained (NFBC1986). In NFBC1966 pregnancies were followed prospectively from the first antenatal contact (10-16th week). After birth, the offspring were examined and then again underwent clinical evaluation at ages 1y, 7y, 14-16y and 31y. At each visit, a wide range of phenotypic, lifestyle and demographic data were gathered by questionnaires and clinical examinations. For the most part, NFBC1986 has undergone similar evaluations to NFBC1966. Linkage to national registries includes hospitalization, deaths, education, medication, pensions, and provides up-to-date demographic and clinical information for members of both cohorts. DNA samples were obtained from 5,923 subjects from NFBC1966 and 6688 subjects from NFBC1986. Data coverage, 96% of all births in 1966 and 99% in 1986, is highly representative for the whole population. The NFBC program comprises more than 20 different projects coordinated by the Center of Lifecourse Disease studies in Northern Finland (COLD) at Oulu University. The prospective data collected from the NFBCs form a unique resource, allowing the study of disease emergence, and of the importance of genetic, biological, social and behavioral risk factors. The genome-wide association (GWA) study sponsored through the STAMPEED program of NHLBI employed genomic DNA samples previously collected by the NFBC1966 study and stored in the DNA repository of the National Institute for Health and Welfare, Finland. This NHLBI sponsored RO1 project aimed to identify genetic variants contributing to metabolic and cardiovascular diseases (CVD). In addition to de-identified genome wide genotypic data, a selected list of phenotypic data related to CVD including weight, height, BMI, HDL, LDL, total cholesterol, triglyceride, glucose, insulin and fasting status, are also available in dbGaP. A summary of the GWAS for the NFBC1966 cardiovascular risk traits can be found in Sabatti et al., Nature Genetics 41: 35-46, 2009, PMID: 19060910. The version 2 release of this study contains sequence data from seventeen loci associated with levels of triglyceride, HDL-C, LDL-C, total cholesterol, fasting plasma glucose, and fasting plasma insulin (Kathiresan et al. 2008, Willer et al. 2008, Sabatti et al. 2009, Dupuis et al. 2010, Teslovich et al. 2010). At each locus, protein-coding regions and 5' and 3' untranslated regions of genes nearest to single nucleotide polymorphisms showing genome-wide significant association with metabolic syndrome-related traits, were sequenced. Targeted Illumina sequencing of 78 genes (~270kb) using 150bp probes was performed on 4943 subjects of the Northern Finland Birth Cohort 1966 (NFBC1966). Whole exome sequencing on the Illumina platform was carried out on 586 of those participants. The sequencing study is part of a larger project that is funded by the National Human Genome Research Institute's Allelic Spectrum in Common Disease Initiative, and comprises sequence data from more than 7000 individuals in two Finnish cohorts: NFBC1966 and the Finland-United States Investigation of NIDDM Genetics (FUSION) study.

  Study phs000276

• The landscape of Usher syndrome-associated transcript isoforms in the human neural retina

  Usher syndrome is an autosomal recessively inherited disorder characterized by the combination of progressive loss of visual function due to retinitis pigmentosa, sensorineural hearing loss and vestibular dysfunction in a subset of cases. Usher syndrome is clinically and genetically heterogeneous. To date, eleven genes have been identified that are associated with Usher syndrome. It is known that these genes express multiple isoforms, however, for most of the known isoforms their relative importance in the human retina is unknown. To fill this gap, using PacBio long-read mRNA sequencing we aimed to provide an overview of the Usher syndrome transcripts in the human retina.

  Study EGAS50000000504

• PROGRESS/ELEMENT DNA Methylation Study

  An extension to the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) birth cohort of Mexico City, the Programming Research in Obesity, GRowth, Environment and Social Stress (PROGRESS) Cohort is an ongoing longitudinal pre-birth cohort, established in 2006 in Mexico City, partnering Icahn School of Medicine at Mount Sinai with Harvard University and the National Institute of Public Health in Mexico, which was designed to study the effects of prenatal exposure to toxic metals, air pollution, phthalates, and stress on childhood development. Pregnant women of 18 years of age and older, pregnant for less than 20 weeks of gestation, had no documentation of heart or kidney disease, no use of steroids or anti-epilepsy drugs, no daily alcohol consumption, had telephone access, and planned to live in Mexico city for the following 3 years, and receiving care through the Mexican Social Security System were initially enrolled (n=1,054). In addition to clinical, demographic and exposure data collected, cord blood was collected to interrogate DNA methylation across the genome for over 300 mother-child dyads. Clinical assessments and exposures were captured during several life stages, including prenatal, infant (0-1 year), youth (1-18 years), and adulthood (mother). The PROGRESS cohort added well-documented phenotyping of children for obesity, metabolic dysfunction, respiratory outcomes, and cardiovascular outcomes, as well as measures of air pollutant, personal care/consumer product, non-chemical stress, and metal mixture exposures. No clinical trials were conducted in this cohort. The data collected in this study should provide a unique resource to investigate DNA methylation as it relates to several environmental exposures and adverse cardiometabolic and neurocognitive health in mothers and children from a prospective birthing cohort. For access to demographic, clinical, and exposure data please directly contact study principal investigators.

  Study phs002754

• Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants

  De novo loss-of-function (LoF) variants in the KMT2A gene are associated with Wiedemann-Steiner Syndrome (WSS). Recently, de novo KMT2A variants have been identified in sequencing studies of cohorts of individuals with neurodevelopmental disorders (NDDs). However, most of these studies lack the detailed clinical information required to determine whether those individuals have isolated NDDs or WSS (i.e. syndromic NDDs). We performed thorough clinical and neurodevelopmental phenotyping on six individuals with de novo KMT2A variants. From these data, we found that all six patients met clinical criteria for WSS and we further define the neurodevelopmental phenotypes associated with KMT2A variants and WSS. In particular, we identified a subtype of Autism Spectrum Disorder (ASD) in five individuals, characterized by marked rigid, repetitive and inflexible behaviours, emotional dysregulation, externalizing behaviours, but relative social motivation. To further explore the clinical spectrum associated with KMT2A variants, we also conducted a meta-analysis of individuals with KMT2A variants reported in the published literature. We found that de novo LoF or missense variants in KMT2A were significantly more prevalent than predicted by a previously established statistical model of de novo mutation rate for KMT2A. Our genotype-phenotype findings better define the clinical spectrum associated with KMT2A variants and suggest that individuals with de novo LoF and missense variants likely have a clinically unrecognized diagnosis of WSS, rather than isolated NDD or ASD alone. This highlights the importance of a clinical genetic and neurodevelopmental assessment for individuals with such variants in KMT2A.

  Study EGAS00001003521

• Family-Based Study on Ulcerative Colitis with Whole Exome Sequencing

  Genetic risk factors for ulcerative colitis are not well understood. We performed a family-based whole exome sequencing analysis to identify potential causal mutations. In the proband, we found a heterozygous de novo mutation in the gene HSPA1L. Our results indicate that the de novo mutation in HSPA1L is associated with ulcerative colitis.

  Study phs001251

• Abnormal_foetal_development_exome_trios

  This project is to explore the contribution of de novo mutations to severe structural malformations diagnosed prenatally using ultrasound. These malformations include heart, CNS, renal and GI abnormalities. In this pilot project we aim to exome sequence 30 parent-foetus trios to ~50X mean coverage and identify de novo functional variants using an algorithm developed in the Hurles group

  Study EGAS00001000167

• Long read data generated for de novo assembly

  Long read data generated for de novo assembly (PacBio and ONT FASTQ files)

  Dataset EGAD50000002367

• Interferon lambda 4 impairs viral antigen presentation and attenuates T cell responses

  Genetic variants of the interferon lambda (IFNL) gene locus are strongly associated with spontaneous and IFN treatment induced clearance of hepatitis C virus (HCV) infections. Individuals with the ancestral IFNL4-dG allele are not able to clear HCV in the acute phase and develop chronic hepatitis C (CHC) with more than 90% probability. Paradoxically, the IFNL4-dG allele encodes a fully functional IFNλ4 protein with antiviral activity against HCV and coronavirus. Here we describe a hitherto unknown effect of IFNλ4 on HCV antigen presentation. Only minor amounts of IFNλ4 are secreted, because the protein is largely retained in the endoplasmic reticulum (ER) where it induces ER stress. Stressed cells were significantly weaker activators of HCV specific CD8+ T cells. This was not due to reduced MHC I surface presentation or extracellular IFNλ4 effects, since T cell responses could be restored by exogenous loading of MHC with HCV antigens. Rather, IFNλ4 induced ER stress impaired HCV antigen processing and/or loading onto the MHC I complex. Our results provide a potential explanation for the IFNλ4 – HCV paradox.

  Study EGAS00001005396

• AML Proteogenomic Landscape Whole-transcriptome RNA-Sequencing

  Whole transcriptome RNA-sequencing of purified bone marrow blasts of 136 de novo, treatment naive AML patients. For further details, we refer to the manuscript "The Proteogenomic Landscape of AML" by Jayavelu, Wolf, Buettner et al. mRNA extraction and whole transcriptome sequencing For transcriptome analysis the TruSeq Total Stranded RNA kit was used, starting with 250ng of total RNA, to generate RNA libraries following the manufacturer’s recommendations (Illumina, San Diego, CA, USA). 100bp paired-end reads were sequenced on the NovaSeq 6000 (Illumina) with a median of 57 mio. reads per sample. RNA Data Analysis Data quality control was performed with FastQC v0.11.9. Reads were aligned to the human reference genome (Ensembl GRCh38 release 82) using STAR v2.6.1. Gene count tables were generated while mapping, using Gencode v31 annotations. All downstream analyses were carried out using R v4.0 and BioConductor v3.12 (Huber et al., 2015; R Core Team, 2020). Size-factor based normalization was performed using DESeq2 v1.28.1(Love et al., 2014).

  Dataset EGAD00001008484

• Genomic profiling of matched well differentiated and de-differentiated liposarcoma.

  Well-differentiated (WD) and de-differentiated (DD) liposarcoma, subtypes of adipocytic sarcomas, are pathologically and clinically dissimilar, but are poorly distinguishable at the molecular level. These tumors harbor neochromosomes formed from amplifications and rearrangements of chr12q. Nineteen selected patients with matched WD and DD tumors underwent extensive exomic and transcriptomic profiling to distinguish genomic features between the two subtypes. Shared point mutations suggest a common tumor origin and de-differentiated tumors have higher burdens of deletions.

  Study EGAS00001002807

• Targeted de-methylation of the FOXP3-TSDR

  CD4+ regulatory T cells (Tregs) are key mediators of immunological tolerance and promising effector cells for immuno-suppressive adoptive cellular therapy to fight autoimmunity and chronic inflammation. Their functional stability is critical for their clinical utility and has been correlated to the demethylated state of the TSDR/CNS2 enhancer element in the Treg lineage transcription factor FOXP3. However, proof for a causal contribution of the TSDR de-methylation to FOXP3 stability and Treg induction is so far lacking. We here established a powerful transient-transfection CRISPR-Cas9-based epigenetic-editing method for the selective de-methylation of the TSDR within the endogenous chromatin environment of a living cell. The induced de-methylated state was stable over weeks in clonal T cell proliferation cultures even after expression of the editing complex had ceased. Epigenetic editing of the TSDR resulted in FOXP3 expression, even in its physiological isoform distribution, proving a causal role for the de-methylated TSDR in FOXP3 regulation. However, successful FOXP3 induction was not associated with a switch towards a functional Treg phenotype, in contrast to what has been reported from FOXP3 overexpression approaches. Thus, TSDR de-methylation is required, but not sufficient for a stable Treg phenotype induction. Therefore, targeted demethylation of the TSDR may be a critical addition to published in vitro Treg induction protocols which so far lack FOXP3 stability.

  Study EGAS00001004867

• A Single Cell Transcriptomic Analysis of Human Neocortical Development

  Defining the number, proportion, or lineage of distinct cell types in the developing human brain is an important goal of modern brain research. We produced single cell transcriptomic profiles for 40,000 cells at mid-gestation to define deep expression profiles corresponding to all known major cell types at this developmental period and compare this with bulk tissue profiles. We identified multiple transcription factors (TFs) and co-factors expressed in specific cell types, including multiple new cell-type-specific relationships, providing an unprecedented resource for understanding human neocortical development and evolution. This includes the first single-cell characterization of human subplate neurons and subtypes of developing glutamatergic and GABAergic neurons. We also used these data to deconvolute single cell regulatory networks that connect regulatory elements and transcriptional drivers to single cell gene expression programs in the developing CNS. We characterized major developmental trajectories that tie cell cycle progression with early cell fate decisions during early neurogenesis. Remarkably, we found that differentiation occurs on a transcriptomic continuum, so that differentiating cells not only express the few key TFs that drive cell fates, but express broad, mixed cell-type transcriptomes prior to telophase. Finally, we mapped neuropsychiatric disease genes to specific cell types, implicating dysregulation of specific cell types in ASD, ID, and epilepsy, as the mechanistic underpinnings of several neurodevelopmental disorders. Together these results provide an extensive catalog of cell types in human neocortex and extend our understanding of early cortical development, human brain evolution and the cellular basis of neuropsychiatric disease.

  Study phs001836

• A novel breast cancer cell line derived from a metastatic bone lesion of a breast cancer patient

  Purpose: We sought to generate and characterize a novel cell line from a breast cancer bone metastasis in order to better study the progression of the disease.Methods: The cell line, P7731, was derived from a metastatic bone lesion of a breast cancer patient and assessed for marker expression. P7731 was analyzed for DNA copy number variation, somatic mutations and gene expression and compared to the primary tumor. Results: P7731 cells are negative for estrogen receptor alpha (ERα), progesterone receptor (PR) and HER2 (triple-negative), strongly express vimentin (100% of cells positive) and also express cytokeratins 8/18 and 19 but at lower frequencies. Flow cytometry indicates P7731 cells are predominantly CD44+/CD49f+/EpCAM-, consistent with a primitive, mesenchymal-like phenotype. The cell line is tumorigenic in immunocompromised mice. Exome sequencing identified a total of 45 and 76 somatic mutations in the primary tumor and cell line respectively, of which 32 were identified in both samples and included mutations in known driver genes PIK3CA, TP53 and ARID1A. P7731 retains the DNA copy number alterations present in the matching primary tumor. Homozygous deletions detected in the cell line and in the primary tumor were found in regions containing three known (CDKN2A, CDKN2B and CDKN1B) and 23 putative tumor suppressor genes. Cell line specific gene amplification coupled with mRNA expression analysis revealed genes and pathways with potential pro-metastatic functions.Conclusion: This novel human breast cancer-bone metastasis cell line will be a useful model to study aspects of breast cancer biology, particularly metastasis-related changes from breast to bone.

  Study EGAS00001002840

• DAC Admixture histories of São Tomé e Príncipe

  Contacts: Paul Verdu +33144057317 paul.verdu@mnhn.fr CNRS-MNHN-Université de Paris UMR7206 Eco-anthropology Jorge M. Rocha jrocha@cibio.up.pt CIBIO Short description The Data Access Committee for acess to genotype and sample information used in the article "Nested admixture during and after the Trans-Atlantic Slave Trade in the island of Sao Tome" by Ciccarella M et al.2025 ensures that data-access requests comply with the Informed Consent provided by donors, and with ethical and deontological guidelines with respect to privacy. Research sampling protocols followed the Declaration of Helsinki guidelines and written informed consent was obtained from all volunteer participants involved in the sampling in São Tomé e Príncipe. The study of the São Tomé e Príncipe sample was undertaken with the support and permission of the Provincial Government of the Ministry of Health of the Democratic Republic of São Tomé e Príncipe, and the Provincial Government of Príncipe. Research sampling protocols also followed the French laws of scientific research deontology (Loi n° 2016-483 du 20 avril 2016) and were approved by the French ethics committees and CNIL (Declaration n°1972648).

  Dac EGAC50000000437

• Smoking-dependent expression alterations in nasal epithelium reveal immune impairment linked to germline variation and lung cancer risk.

  Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to lifestyle risk in the form of cigarette smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, often many years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk are unclear. CT screening of current and former smokers has been shown to reduce lung cancer mortality by up to 26%. To examine whether clinical risk stratification can be improved upon by the addition of genetic data, and to explore the mechanisms of the persisting risk in former smokers, we have analyzed transcriptomic data from accessible airway tissues of 487 subjects. We developed a model to assess smoking associated gene expression changes and their reversibility after smoking is stopped, in both healthy subjects and clinic patients. We find persistent smoking associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune and interferon related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier. Our results provide initial evidence for germline-mediated personalised smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality.

  Dac EGAC50000000169

• High-depth whole genome sequencing of 26 premalignant breast lesions

  Ductal carcinoma in situ (DCIS) is a non-obligate precursor lesion of breast cancer, representing 20-25% of newly diagnosed breast cancer lesions. It is currently not possible to predict which DCIS patients will progress to invasive breast cancer. The samples deposited here are part of a larger study using high-depth whole-genome sequencing (WGS) to investigate the somatic mutation genomic landscape of DCIS. Comprehensive evaluation of DCIS genomes aims to uncover biological insights into breast cancer progression and potential opportunities to stratify DCIS patients for personalised treatment options or active surveillance. Due to specific restrictions imposed by the ethical approval at sample collection, the use of the germline data is restricted to filtering of somatic mutation calls only and cannot be used outside this purpose.

  Study EGAS50000001559

• scRNA-seq of total bone marrow and T cells from multiple myeloma long-term survivors

  scRNA This dataset contains 50 scRNA-seq samples from bone marrow aspirates of 11 multiple myeloma patients experiencing long-term survival and 3 healthy donors. For each donor, total bone marrow and CD3+ T cells were sequenced. For multiple myeloma patients, paired samples were collected at initial diagnosis and between 7-17 years after first-line therapy. Bone marrow mononuclear cells were isolated by Ficoll density gradient centrifugation. For sorting of total bone marrow cells singlet, live cells were gated and sorted, for sorting of T cells CD45+, CD3+ cells were gated and sorted on either FACSAria Fusion or FACSAria II. Single-cell RNA sequencing were generated using 10x Genomics single-cell RNAseq technology (Chromium Single Cell 3’ Solution v2) according to the manufacturer’s protocol and sequenced on an Illumina HiSeq4000 (paired end, 26 and 74 bp). Bulk RNA Singlet, live CD3+CD4- CXCR3+CD8+ and CD3+CD4- CXCR3-CD8+ cells were sorted from 7 bone marrow and 3 peripheral blood samples of 7 multiple myeloma patients using a FACSAria Fusion machine. Bulk-RNA sequencing libraries were generated using the SMART Seq Stranded Total RNA-Seq kit (Takara) and sequenced using the Illumina NovaSeq 6000 platform (2 x 100 bp).

  Dataset EGAD00001010025

• Influence of the Microbiome on Epigenetic Mechanisms in IBD

  Live CD4 T cells were sorted from inflamed and non-inflamed tissue samples of IBD patients or from healthy and IBD blood samples. ATAC-Seq libraries were generated from live CD4 T cells sorted from i) inflamed and non-inflamed tissue samples, ii) healthy and IBD blood samples, or from iii) CD4 T cell subsets polarised from healthy blood samples. After isolating crude nuclei, live CD4+ T cells were treated with Tagment DNA buffer and Tagment DNA Enzyme (Nextera DNA Library Prep Kit, Illumina), and then the DNA was purified by MinElute PCR Purification Kit (Qiagen). Transposed DNA fragments were amplified using specific adapters followed by purification with MinElute PCR Purification Kit (Qiagen). Fragments from 240-360pb were selected in the PippinHT system (Sage Science). The quality of the library and its DNA concentration were assessed by Bioanalyzer instruments (Agilent Technologies) and ultimately submitted for sequencing using Illumina HiSeq 2500 sequencer, V4 chemistry. On the other hand, single cell RNA-Seq libraries were generated exclusively from inflamed and non-inflamed tissue samples of Crohn’s disease patients. Briefly, live CD4 T cells were captured and encapsulated before cDNA amplification using the 10X Genomics Chromium Platform. Samples were prepared as outlined by 10x genomics Single Cell 3’ Reagent Kits v2 user guide. Samples were sequenced on a HiSeq 2500 with the following run parameters: Read 1 – 26 cycles, read 2 – 98 cycles, index 1 – 8 cycles.

  Dataset EGAD00001011066

• Comprehensive de novo variant discovery with HiFi long-read sequencing

  We performed whole-genome sequencing of 8 trios with intellectual disability using Pacbio HiFi long-reads. We then called variants with PBSV and Deepvariant. We filtered for high-quality de novo variants and validated them.

  Study EGAS00001006479

• NHGRI GREGoR Consortium: Genomics Research to Elucidate the Genetics of Rare Disease

  The NHGRI GREGoR (Genomics Research to Elucidate the Genetics of Rare Disease) Consortium was established in June 2021 with the goal of developing novel tools and approaches to advance the discovery of the genetic basis of rare conditions. Numerous types of molecular data are generated in GREGoR and available on the AnVIL cloud platform via dbGaP application, including short- and long-read genome and exome sequencing, transcriptomics, metabolomics, methylomics, and proteomics. De-identified clinical and demographic data is obtained, with a focus on standardized ontologies.Visit the GREGoR Consortium data webpage for summary information about the GREGoR Dataset, including numbers of participants and data types, methods documentation, and Release Notes. The Consortium comprises five Research Centers (RCs - see below), a Data Coordinating Center (DCC), and various partner members and external collaborators.Baylor College of Medicine Research Center (BCM-GREGoR) The Baylor College of Medicine GREGoR program, which is part of the GREGoR consortium, enrolls individuals, families, and cohorts with suspected rare disease across a range of syndromic and non-syndromic phenotypes. Subjects are enrolled from national and international collaborating physician referrals. Subjects provide written informed consent for future re-contact. Data generated and shared include family structure, detailed phenotypes, exome or short-read genome data, and in some cases long-read genome or RNA-sequencing, and these are shared upon completion of standard quality control checks and annotation. Broad Institute (Broad) The Broad Center for Mendelian Genomics, part of the GREGoR consortium uses next-generation sequencing (exome, genome, transcriptome, and long read sequencing), computational approaches, and functional studies to discover the variants and genes that underlie Mendelian conditions with a particularly focus on neuromuscular, neurodevelopmental, and syndromic phenotypes. Samples come from collaborators and direct enrollment through the Rare Genomes Project and we are committed to rapid data sharing without an embargo period. University of California, Irvine (UCI-GREGoR) To accelerate the pace of Mendelian disease gene discovery and clinical implementation, we propose a Mendelian Genomics Research Center, part of the GREGoR Consortium, leveraging the broad pediatric and adult clinical and research expertise at Children's National Hospital and University of California, Irvine. Our goal is to develop best practices to increase the diagnostic yield of rare diseases, engage the community to reduce health disparities for complex diagnoses, while creating a dataset accessible to all. Our Center will unite world class experts combining basic and translational research with innovative approaches to phenotyping, variant identification and functional investigation of both coding and non-coding sequence changes with the goals of discovering novel Mendelian gene variations and identifying variants not detected on current sequencing pipelines, disambiguating uncertain variants into disease-causing versus benign categorizations, and sharing information by working collaboratively with the GREGoR community.GREGoR Stanford Site (GSS) The goal of the GREGoR Stanford Site (GSS) is to provide a platform for functional genomics research and validation to improve diagnosis in Mendelian disease. Participants included individuals with undiagnosed suspected Mendelian disease who had non-diagnostic exome sequencing and their immediate family members. Participants and their family members provided written, informed consent and biological samples from which DNA, RNA, plasma, fibroblasts, PBMCs and other cell types were generated and stored. Samples from research participants and their immediate family members may have undergone short and long-read genome sequencing, transcriptome sequencing, metabolomics and/or lipidomics profiling, methyl-capture-sequencing and ATAC-sequencing. De-identified clinical data extracted from participant medical records are linked to the samples. University of Washington Center for Rare Disease Research (UW-CRDR) The goals of the University of Washington Center for Rare Disease Research are to: (1) maximize novel gene discovery for Mendelian conditions by recruitment, short- and long-read whole genome sequencing, transcriptome sequencing and analysis of families with rare conditions for which the gene is either unknown or the gene is known but no pathogenic variant can be identified via clinical testing; (2) develop new strategies for gene discovery for Mendelian conditions caused by variants that are difficult to detect using conventional testing strategies, variants of unknown function effect (e.g., regulatory, structural variants) or have unusual modes of inheritance; and (3) implement high-throughput screening and targeted follow-up functional studies to prioritize and validate candidate non-coding variants. De-identified data and phenotypic information are shared via MyGene2, ClinVar, and AnVIL.

  Study phs003047