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• CRC and UC WES samples

  This is the dataset used to produce results for the report "NOUS-209 off-the-shelf immunotherapy has the potential to hit primary and metachronous colorectal and urothelial cancer in Lynch syndrome"

  Dac EGAC50000000782

• Systematic Analysis of Coding and Non-coding Elements in Developmental Pathways Implicated in Holoprosencephaly Pathogenesis

  We applied targeted capture to examine 153 genes representative of all the major vertebrate developmental pathways among 340 probands and 285 of their unaffected parents to rank their relative significance as causes for holoprosencephaly (HPE).

  Study phs001653

• Whole Exome Sequencing Identifies

  Combined Immunodeficiency with Multiple Intestinal Atresias (CID-MIA) is a rare genetic disorder with the cause previously unknown. Symptoms of CID-MIA include atresias in the small and/or large intestine, as well as immunodeficiency. In this study, we sequenced the whole exome of 5 unrelated CID-MIA patients as well as their healthy family members, and identified deleterious homozygous or compound heterozygous mutations in the gene TTC7A in all the 5 patients, as well as in 3 additional patients with Sanger sequencing. Our findings strongly indicate TTC7A dysfunction to be the cause for CID-MIA.

  Study phs000641

• Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for sequencing. 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/.

  Dataset EGAD00001006610

• Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for sequencing. 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/ .

  Dataset EGAD00001006612

• Tracking the evolution of esophageal squamous cell carcinoma under dynamic immune selection by multi-omics sequencing

  Intratumoral heterogeneity (ITH) has been linked to decreased efficacy of clinical treatments. However, although genomic ITH has been characterized in genetic, transcriptomic and epigenetic alterations are hallmarks of esophageal squamous cell carcinoma (ESCC), the extent to which these are heterogeneous in ESCC has not been explored in a unified framework. Further, the extent to which tumor-infiltrated T lymphocytes (TILs) are directed against cancer cells, but how the immune infiltration acts as a selective force to shape the clonal evolution of ESCC is unclear. In this study, we perform multi-omic sequencing on 186 samples from 36 primary ESCC patients. Through multi-omics analyses, it is discovered that genomic, epigenomic, and transcriptomic ITH are underpinned by ongoing chromosomal instability. Based on the RNA-seq data, we observe diverse levels of immune infiltrate across different tumor sites from the same tumor. We reveal genetic mechanisms of neoantigen evasion under distinct selection pressure from the diverse immune microenvironment. Overall, our work offers an avenue of dissecting the complex contribution of the multi-omics level to the ITH in ESCC and thereby enhances the development of clinical therapy.

  Dataset EGAD00001009482

• Machine learning to detect the SINEs of cancer

  We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA (cfDNA) through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a novel machine-learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to samples from 5108 individuals, 2037 with cancer and the remainder without cancer. Samples from cancer patients and controls were pre-specified into four cohorts used for: 1) model training, 2) analyte integration and threshold determination, 3) validation, and 4) reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the Validation Cohort, at a specificity of 98.5%. Combining A-PLUS with aneuploidy and 8 common protein biomarkers detected 51% of 1167 cancers at 98.9% specificity. We found that part of the power of A-PLUS could be ascribed to a single feature – the global reduction of AluS sub-family elements in the circulating DNA of cancer patients. We confirmed this reduction through the analysis of another independent dataset obtained with a very different approach (whole genome sequencing). The evaluation of Alu elements therefore has the potential to enhance the performance of several methods designed for the earlier detection of cancer.

  Study EGAS00001007169

• University of Washington Cerebrospinal Fluid Biomarker Study for Parkinson disease

  There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis and monitoring disease progression. In this study we evaluated cerebrospinal fluid (CSF) proteins, which are known to be critically involved in PD or identified in our preliminary profiling studies, aptamers, and RNAs as potential PD biomarkers. Access to subjects for this study was via the Pacific Northwest Udall Center (PANUC) and the Alzheimer's Disease Research Center (ADRC) at the University of Washington and Oregon Health and Sciences University (OHSU). Using CSF samples from 30 well-characterized patients with PD and 30 age-, sex-matched healthy controls, we prepared RNA seq libraries and performed deep sequencing of all RNA species, including small and long RNA, mRNAs, noncoding RNAs and differentially spliced transcripts. We then tried several methods for RNAseq data analysis to optimize our analysis pipeline. We identified a total of 3381 transcripts corresponding to 182 long intergenic RNAs (LincRNAs), 11 microRNAs (miRNAs), 2861 protein-coding transcripts, 200 pseudogenes and 127 antisense RNAs; some of them were differentially expressed between PD and control groups. Selected differentially expressed RNAs have been validated in the same set of CSF samples using real-time PCR (RT-PCR). Further validations in independent, larger cohorts of samples are still ongoing. Our results obtained so far suggested that CSF proteins and RNAs could be used as good indexes for PD diagnosis and disease severity/progression. This study is a part of the NIDDS-funded Parkinson's Disease Biomarkers Program (PDBP).

  Study phs000901

• Epigenetic Biomarkers of Aging

  The aim of the study was to discover new epigenetic biomarkers of aging. We used a genome-wide screen for genetic loci showing consistent changes of DNA methylation with progressive aging. Blood DNA samples from 19 apparently healthy individuals aged 22-80 years obtained from the NINDS repositories were analyzed for DNA methylation using Reduced Representation Bisulfite Sequencing. We followed the New England Biolabs (NEB) protocol for methylated adaptors as described previously. Briefly, 1 microgram of genomic DNA was spiked with 100 picograms of lambda phage DNA as the unmethylated standard and digested with MspI endonuclease at C’CGG sites. Ends of restriction fragments were filled in, 3’-dA tailed and methylated adaptors were ligated to the ends of restriction fragments. Bisulfite treatment using the Epitect kit (Qiagen) followed. Bisulfite-converted libraries were amplified using EpiMark Taq DNA polymerase (NEB) and primers with dual barcode indices. The libraries were pooled and sequenced on Illumina HiSeqX instrument using paired end reads of 150 bases. We used Bismark v0.23.1 to align the sequences to hg19 human genome assembly. We used methylKit v1.22.0 to analyze differential methylation in individuals of different ages.

  Study phs003046

• BAP1 study

  Background: Mutations in BAP1 have been identified in many aggressive cancers. Current therapeutic strategies for BAP1-deficient tumors are not effective. Goal: Discover novel strategies for BAP1-deficient tumors. Details: In our study, we identified a potential therapeutic strategy for BAP1-deficient cancers. We used multi-omics approaches to understand the underlying mechanisms behind why the discovered potential therapeutic strategy is effective.

  Study EGAS50000000235

• Kids First: Genomic Etiologies of CHARGE Syndrome, Related Conditions and Structural Anomalies

  Developmental disorders with structural birth defects account for the majority of morbidity and mortality in children's hospitals, and the genetic bases of many clinical phenotypes remain unknown. Genetic testing for individuals with structural malformations has uncovered the basis of many such birth defects; however, many more cases remain unsolved, posing challenges for diagnosis, treatment, and prevention. Multiple anomaly conditions are particularly challenging to diagnose, since they often present with unique combinations of clinical features that vary widely between affected individuals, even in the same family. CHARGE Syndrome (Coloboma of the eye, Heart Defects, Atresia of the choanae, Retardation of growth and development, Genital abnormalities including pubertal delay and infertility, Ear abnormalities with deafness and vestibular disorders) is a multiple anomaly condition that affects a wide variety of organ systems. CHARGE Syndrome is caused in most cases by monoallelic pathogenic variants in CHD7, the gene encoding ATP-dependent helicase chromodomain DNA binding protein 7. Both de novo and inherited variants in CHD7 have been reported in CHARGE, and a growing number of families present with individuals who test positive for a pathogenic CHD7 variant yet exhibit only mild features. Similarly, individuals with CHARGE Syndrome often exhibit broad variability and reduced penetrance of clinical features, consistent with pleiotropic roles for CHD7 during development and/or additional genetic contributors or modifying alleles. Recent work has also implicated RERE, KMT2D, EP300, and PUF60 in having a role in CHARGE Syndrome.We hypothesize that (1) some cases of CHARGE are due to other genetic etiologies including oligogenicity, and (2) genetic modifiers contribute to the broad clinical variability and reduced penetrance of CHARGE features. To address these hypotheses, we have generated a cohort of 223 deeply clinically phenotyped individuals with CHARGE Syndrome and related disorders and structural anomalies who tested negative by chromosomal microarray, single gene sequencing, next generation panel sequencing, or exome sequencing. These individuals exhibit clinical CHARGE-like features including structural birth defects affecting craniofacial, ocular, neurosensory, brain, heart, mediastinal, renal, genitourinary, and skeletal organs. Our cohort includes these 223 individuals as well as affected and unaffected family members who consented to clinical and research genetic testing and donated blood samples for DNA and RNA isolation and sequencing. Building on this valuable cohort, we propose to use exome and genome sequencing to identify novel genetic etiologies of CHARGE and related developmental disorders for which alternative genetic tests have been inconclusive. Identification of novel pathogenic genetic variants and contributing modifier alleles within the coding and non-coding portion of the genome of these individuals will improve genetic diagnosis and provide important insights toward understanding the developmental mechanisms of structural birth defects.

  Study phs002592

• Identification of G-Quadruplex Clusters by High-Throughput Sequencing of Whole-Genome Amplified Products with a G-Quadruplex Ligand

  G-quadruplex (G4) is a non-canonical DNA structure that has been found in the genome. To identify clusters of G4-forming sequences in the genome, we performed whole genome amplification (WGA) in the presence or absence of a G4 ligand that inhibits DNA polymerase activity on the G4 forming regions, followed by high-throughput sequencing of the WGA products. As the results, 12254 G4 cultures were identified on HeLa genomic DNA.

  Study phs001450

• iNeuron_RNAseq

  Characterisation of a timecourse of differentiation of induced cortical excitatory neurons generated by overexpression of the Ngn2 transcription factor transgenically in BOB iPSCs. The aim is to understand the differentiation trajectory undergone in this process, and characterise the transcriptome in these cells for further disease modelling. 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 EGAS00001004238

• Profiles of Extracellular RNA in Cerebrospinal Fluid and Plasma from Subarachnoid Hemorrhage Patients

  Brain injury resulting from hemorrhagic stroke is clinically challenging to manage and results in high rates of morbidity and mortality. The pathophysiology of brain damage resulting from aneurysmal subarachnoid hemorrhage (aSAH) is largely unknown, and methods to treat and monitor patients are variable with no meaningful correlations to patient outcome. Prediction of patient risk for serious neurological complications is currently a significant clinical obstacle. An extracellular RNA (exRNA) biomarker to predict onset and severity of brain damage would improve patient outcomes. We sequenced plasma and CSF samples from adult patients with SAH. Samples were collected from post bleed day 1 to day 7. Total exRNA was isolated from each sample. In addition, we prepared a subset of 140 CSF samples, isolating the RNA contained within extracellular vesicles and vesicle-depleted biofluid.

  Study phs001759

• Profiling the genomic landscape and evolutionary history of polyploid giant cancer cells in undifferentiated pleomorphic sarcomas

  In this study, we characterise PGCCs in ten pleomorphic sarcomas and use topographic single-cell DNA sequencing (scDNA-seq) to investigate their genomic landscape. We selected PGCCs based on their nuclear morphology, including mononucleated or multinucleated bizarre, misshapen nuclei, and analysed them at single-cell resolution. Histopathological analysis showed that PGCCs were often randomly distributed throughout the tumour and did not appear in clusters, suggesting that they arise de novo rather than through clonal expansion. scDNA-seq revealed that PGCCs originate from the dominant tumour population and exhibit extensive copy number heterogeneity, either due to subsequent or ongoing chromosomal instability. Both clonal and subclonal chromothripsis-like events were identified in PGCCs, indicating that chromothripsis is a key driver of heterogeneity in these cells and is linked to multinucleation rather than mononuclear PGCC formation.

  Dataset EGAD50000002084

• Genome-wide prediction of human embryos

  BACKGROUND: Preimplantation genetic diagnosis (PGD) enables profiling of embryos for genetic disorders prior to implantation. The majority of PGD testing is restricted in the scope of variants assayed or by the availability of extended family members. While recent advances in single cell sequencing show promise, they remain limited by bias in DNA amplification and the rapid turnaround time (<36 h) required for fresh embryo transfer. Here, we describe and validate a method for inferring the inherited whole genome sequence of an embryo for preimplantation genetic diagnosis (PGD). METHODS: We combine haplotype-resolved, parental genome sequencing with rapid embryo genotyping to predict the whole genome sequence of a day-5 human embryo in a couple at risk of transmitting alpha-thalassemia. RESULTS: Inheritance was predicted at approximately 3 million paternally and/or maternally heterozygous sites with greater than 99% accuracy. Furthermore, we successfully phase and predict the transmission of an HBA1/HBA2 deletion from each parent. CONCLUSIONS: Our results suggest that preimplantation whole genome prediction may facilitate the comprehensive diagnosis of diseases with a known genetic basis in embryos.

  Study EGAS00001001020

• Biallelic variants in the non-protein coding minor spliceosome components RNU6ATAC and RNU6ATAC cause syndromic monogenic autoimmune diabetes

  Non-protein coding genes are emerging as critical contributors to the aetiology of rare diseases, providing key insights into human biology and uncovering novel disease mechanisms. We identified 7 individuals from 4 families with early-onset diabetes (diagnosed <5 years) and immune dysregulatory features caused by biallelic variants in RNU6ATAC. RNU6ATAC encodes a small nuclear RNA (snRNA) acting as a catalytic component of the minor spliceosome, a protein-RNA complex mediating splicing of ~700 genes containing U12/minor-type introns. Variant screening of the other 64 minor spliceosome genes in 276 infants with diabetes identified 12 unrelated individuals with biallelic disease-causing variants in RNU4ATAC. Biallelic pathogenic RNU4ATAC variants are known to cause a variable spectrum of clinical features, which until now did not include diabetes. Clinically, 12/19 RNU6ATAC/RNU4ATAC patients had additional immune dysregulatory features, and 50% of patients tested were islet-autoantibody positive, strongly supporting an autoimmune aetiology for their diabetes. RNA-seq in 3 individuals with biallelic RNU6ATAC variants showed a pattern of intron retention in U12 intron-containing genes similar to that seen in RNU4ATAC-individuals (n=3), supporting a shared disease mechanism. Analysis of patients’ transcriptomic, methylation and immune data revealed impaired B cell development and maturation. We conclude that biallelic RNU6ATAC variants cause a novel syndrome of early-onset autoimmune diabetes and immune dysregulation. We further show that infancy-onset diabetes is a previously unrecognised feature of RNU4ATACopathy. Our work highlights the important role of two snRNAs critical to minor spliceosome function in immune system regulation, providing novel insights into the pathogenesis of autoimmune diabetes.

  Study EGAS50000001565

• Resuscitation Outcomes Consortium Pragmatic Trial of Airway Management in out-of-Hospital Cardiac Arrest (ROC PART-BioLINCC)

  Data Access NOTE: Please refer to the &#8220;Authorized Access&#8221; section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To determine the effect of an initial airway management strategy using laryngeal tube (LT) insertion, compared with endotracheal intubation (ETI), on survival among adults with out-of-hospital cardiac arrest (OHCA).Background: Out-of-hospital cardiopulmonary arrest (OHCA) affects more than 350,000 adults in the United States each year, with only a low percentage of patients surviving to hospital discharge. Emergency medical services (EMS) paramedics commonly perform ETI or insertion of supraglottic airways (SGAs), such as the LT, on patients with OHCA to facilitate oxygenation and protect the lungs from aspiration of vomitus. Because SGA insertion is rapid, simple, and requires less training compared to ETI, many EMS agencies have incorporated this as the primary method of ventilation during OHCA resuscitation. However, the optimal method for OHCA advanced airway management is unknown.Participants: A total of 3004 patients were included; 1505 assigned to initial LT and 1499 assigned to initial ETI.Design: PART was a multicenter cluster-crossover randomized trial. The trial included 27 EMS agencies associated with US sites of the Resuscitation Outcomes Consortium (ROC). The EMS agencies were grouped into 13 randomization clusters. Each cluster selected a crossover interval of 3 or 5 months. Within each cluster, treatment assignments for consecutive intervals were computer-randomized in blocks of 2 to ensure balanced exposure to both airway groups. Crossovers between study groups could occur more than once. Treatment assignments were initial LT insertion or initial ETI. Neuromuscular blocking agents or video laryngoscopy was permitted for initial intubation efforts. The trial did not limit the number of initial LT insertion or ETI attempts. If the initial insertion efforts were unsuccessful, EMS personnel performed rescue airway management using any available airway technique. EMS personnel followed local protocols for confirmation of airway placement and management of OHCA, including field termination of resuscitation efforts. Patients receiving bag-valve mask (BVM) ventilation only were retained in their assigned treatment group per intention-to-treat principles. The trial did not prescribe clinical care at the receiving hospitals, including use of EMS airway, targeted temperature management, percutaneous coronary intervention, or the timing of withdrawal of life-sustaining therapy.The primary outcome was 72-hour survival. Secondary outcomes included return of spontaneous circulation, survival to hospital discharge, and favorable neurological status at hospital discharge (Modified Rankin Scale score &#8804;3). Conclusions: Among adults with OHCA, a strategy of initial LT insertion was associated with significantly greater 72-hour survival compared with a strategy of initial ETI. These findings suggest that LT insertion may be considered as an initial airway management strategy in patients with OHCA, but limitations of the pragmatic design, practice setting, and ETI performance characteristics suggest that further research is warranted.

  Study phs003902

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__Colorectal_LCM

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003455

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__clear_cell_renal_cell_carcinoma___2

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003542

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__clear_cell_renal_cell_carcinoma

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001002608

• Genes-Environments and Admixture in Latino Asthmatics (GALA II) Study

  A case-control pharmacogenetic study of bronchodilator drug response among racially admixed Latino children with asthma. Each participant had two spirometry measurements using the KoKo PFT System. With the first spirometry test, participant was administered with 4 puffs of HFA Albuterol. The second albuterol measurement was based on age, for participants under 16 years of age, additional 2 puffs were administered and for those over 16 years of age, additional 4 puffs were administered. The overall goal is to identify genetic factors which are predictive of drug response in children with asthma. The principal tools include a questionnaire and biological specimen collection. Participants are 8-21 years old at time of recruitment. Children with asthma have physician-diagnosed asthma, symptoms and medications. The GALAII Study is utilized in the following dbGaP substudies. To view genotypes, analysis, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" box located on the right hand side of this top-level study page phs001180 GALAII Study. phs001274phs001274 GALAII GWAS

  Study phs001180

• RNA Splicing Dysregulation in the Pathogenesis of Chronic Lymphocytic Leukemia

  RNA splicing dysregulation is a hallmark of cancers, promoting the onset and progression of disease. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occurs in approximately 20% of patients. However, the underlying mechanism for splicing defects in spliceosome unmutated CLL cases remains elusive. To discover posttranscriptional regulation of RNA splicing, we performed RNA sequencing using RNA derived from B cells from 6 healthy donors and 36 CLL patients, along with MAZTER sequencing from 9 CLL patients (8 matched with RNA sequencing cohort) and B cells from 5 healthy donors. We found that CLL cells have dysregulated m6A modification sites on transcripts from splicing factors, suggesting a critical role of m6A modification in RNA splicing dysregulation.

  Study phs003191

• WXS of 147 lung cancer patients treated with immunotherapy

  We first attempted to predict MHC-binding neoantigens at high accuracy with convolutional neural networks. This prediction model outperformed previous methods in &gt; 70% of test cases. Importantly, our method remarkably increased the predictive value of neoantigen load especially in combination with known resistance parameters. We then developed a classifier that can predict resistance from point mutations that are deleterious to protein function. Notably, genes involved in the adaptive immune response, cytokine signaling,and EGFR signaling held high explanatory power. Furthermore, when integrated with our neoantigen profiling, these anti-immunogenic mutations revealed significantly higher predictive power than known resistance factors.

  Study EGAS00001003781

• Pathogenic Neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

  Neurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. Therefore, a targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants. an in-house developed tool (QURNAS) was used to calculate the enrichment score (ERS) for each splicing event. RNA enrichment of NF1 and SPRED1 was done using SPET (NUGEN - NF1 only) and using SureSelect (Agilent - NF1 and SPRED1).

  Study EGAS00001005530