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• Pediatric Whole Genome Sequencing Diagnostic Utility

  The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. We compared diagnostic rate of WGS to CMA and targeted gene testing of 100 patients referred to The Hospital for Sick Children Genetics clinic in 2014. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In an additional 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling.

  Study EGAS00001001623

• PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice

  The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2, a gene encoding a putative RNA-binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects respectively. PATL2's amphibian orthologue is involved in the regulation of oocyte mRNA as a partner of CPEB. However, Patl2's expression profile throughout oocyte development in mice, alongside colocalisation experiments with Cpeb1, Msy2 and Ddx6 (three oocyte RNA-regulators) suggest an original role for Patl2 in Mammals. Accordingly, transcriptomic analysis of oocytes from WT and Patl2-/- animals demonstrated that in the absence of Patl2, expression levels of a select number of highly relevant genes involved in oocyte maturation and early embryonic development are deregulated. In conclusion, PATL2 is a novel actor of mammalian oocyte maturation whose invalidation causes OMD in humans.

  Study EGAS00001002903

• VCRC Imaging Protocol for Magnetic Resonance and Positron Emission Tomography in Large-Vessel Vasculitis (Takayasu's Arteritis): Development as Clinical Trial Outcome Measures Vasculitis Clinical Research Consortium

  Takayasu's arteritis is a rare disease that affects the blood vessels. Takayasu's arteritis can cause swelling of large and medium-sized blood vessels. The blood vessels that are commonly affected are the branches of the aorta (the main blood vessel that leaves the heart). The purpose of this study is to help doctors learn more about this disease by using x-ray like tests to see if they are helpful in taking care of patients with Takayasu's arteritis. This is an imaging study that compares x-ray-like tests that would not be a part of your regular care (PET/CT) with x-ray-like tests that are a part of your regular care (MRI). At two visits, three months apart, patients will have a PET/CT scan performed at the same time as their MRI scan; some patients will also have a third PET/CT scan. A total of 36 people with Takayasu's arteritis at several hospitals will take part in this study. Doctors will use images from the different time points, along with information from exams and symptoms, to learn more about the disease.

  Study phs001715

• Genomics and Epigenomics of the Elderly Response to Pneumococcal Vaccines

  Pneumococcal Vaccine Study: This is a study designed to develop a detailed transcriptional and cellular profile of the immune response to pneumococcal vaccination with conjugated and non-conjugated polysaccharide vaccines in the senescent immune system of older adults. In this study, 39 healthy adults ages 60 and older that have never received pneumococcal vaccination, have been randomized to receive Prevnar 13 (Pfizer), a conjugated 13-valent vaccine or Pneumovax 23 (Merck), a non-conjugated 23-valent vaccine. Four (4) study visits occurred over 70 days at Day -7 (baseline), day 1, day 10 and day 60 (± 5d) post vaccination.Bulk RNA-sequencing data are available on the 4 time points for 31 of the participants and 1 replicate. ATAC-Doublet Detector Study: We generated single nucleus ATAC-seq (snATAC-seq) data from PBMCs of 2 baseline blood samples from the pneumococcal study. Generated data was then used to benchmark a novel computational method for detecting multiplets in snATAC-seq data, namely, AMULET (https://github.com/UcarLab/AMULET). Multiplets confound downstream analyses by introducing combined epigenomic profiles from 2 or more cells/nuclei. AMULET detects multiplets by using unique snATAC-seq data features that allow it to reliably use read counts to detect multiplets for their removal from data analyses.

  Study phs002361

• A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells

  Molecular heterogeneity of tumors, epigenetic changes and a diverse range of molecular mechanisms are main contributors to drug resistance, which represents one of the great challenges in cancer treatment. A deeper understanding of the molecular biology of cancer has resulted in better targeted therapies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has to some extent also been observed in colorectal cancer (CRC) patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block resistance. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant CRC cells as a well-define model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both well-known and novel responses. We primarily observe widespread upregulation of tyrosine kinases (RTKs) and and metabolic pathways. This points to by which the treated cells switch energy sources as a defensive response entering a quiescent like state, while activating signalling to re-activate the MAPK pathway.

  Study EGAS00001002654

• fragmentomic features of individuals with different cfDNA concentrations

  The uploaded data includes sequencing data of 862 individuals from the nasopharyngeal carcinoma (NPC) screening study. Samples from this cohort were sequenced using targeted sequencing methods for the Epstein Barr Virus (EBV) and selected autosomal DNA, but only ‘off-target’ reads were used for fragmentomic analyses. We have also performed genome-wide (non-targeted sequencing) for 1) Individuals with the highest and lowest cell-free DNA concentration (40 individuals); 2) A subsequent collection of the subjects with the highest and lowest DNA concentrations after six years (26 individuals); 3) 30 cases of pregnancy and 4) 20 patients with hepatocellular carcinoma. All sequencing data are of extracted plasma cfDNA from human subjects. The targeted sequencing samples from 862 individuals were sequenced on the NextSeq500 System (Illumina) and aligned to the EBV genome (AJ507799.2) and the human genome (hg19). The alignments were provided in bam format. The original fastq files of the remaining non-target sequencing samples were provided.

  Dataset EGAD50000000970

• Single cell targeted DNA-sequencing (and antibody sequencing) of high hyperdiploid B-ALL

  This dataset contains all sequencing data of the publication "Single-cell DNA and Surface Protein Characterization of High Hyperdiploid Acute Lymphoblastic Leukemia at Diagnosis and During Treatment". We provide both the raw fastq-files as well as the processed data in the form of .h5 files. There are 13 patients: XJ176, XH135, XJ180, XI145, XI148, XI167, XI150, XJ175, XJ178, XI162, XF98, XG111 and XG115. Of 9 patients, also follow-up samples during/after treatment were sequenced: XJ180, XI145, XI148, XI167, XI150, XJ175, XJ178, XI162 and XG111. To identify the cell types and distinguish between normal and leukemic cells, cell surface proteins were also captured for 6 samples: XF98, XG111 (at diagnosis and during treatment), XG115, XI162 (after treatment) and XJ175 (after treatment). All samples were processed on the MissionBio platform with a custom amplicon panel, and DaB-seq for the combined targeted DNA and protein sequencing.

  Dataset EGAD50000000829

• Metabolic reprogramming towards OXPHOS identifies a novel therapeutic target for mantle cell lymphoma

  Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomics analysis of clinical specimens, we show that metabolic reprogramming towards oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton’s tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), an incurable B-cell lymphoma with poor clinical outcomes. Inhibition of OXPHOS with a novel, clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in significant growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies.

  Dataset EGAD00001004577

• 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

• Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic

  Somatic mutations of RUNX1, which encodes the myeloid and lymphoid transcriptional factor RUNX1, are common in both B- and T- acute lymphoid leukemia (ALL) and are associated with poor prognosis of T-ALL. However, there has been no comprehensive investigation of the pattern or prevalence of RUNX1 germline mutation in both B- and T-ALL. Here we report germline RUNX1 variants in 1.23% of B-ALL and 2.11% of T-ALL, identifying 31 unique variants in 62 B-ALL and 18 unique variants in 26 T-ALL children. The majority of frameshift and nonsense variants affected RUNX1 function in transcriptional regulation, hematopoiesis, and cellular proliferation. We identified JAK3 as the most frequent somatic mutation in T-ALL with RUNX1 variants. These results not only identify RUNX1 as a leukemia predisposition gene but also further underline the importance of germline genetic variants to the development of ALL

  Dataset EGAD00001007793