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• RNA sequencing and whole-genome mate-pair sequencing of osteosarcoma

  This data set includes 72 mate pair sequenced osteosarcomas (36 as part of a discovery cohort and 36 as part of a validation cohort). It also includes RNA-sequencing data on 67 osteosarcomas (mostly overlapping with the above mate pair sequenced cases) and 13 osteoblastomas used as controls for gene expression levels.

  Dataset EGAD00001005307

• DNA methylation-based classification of sinonasal tumors [DNA sequencing]

  This dataset contains raw exome sequencing data from nine sinonasal undifferentiated carcinoma FFPE samples and matched normal tissue that were assigned to a shared epigenetic class using DNA methylation-based classification. They were analyzed using the Twist Human Core Exome Plus Kit (Twist Bioscience) on a NovaSeq 6000 sequencer.

  Dataset EGAD00001009668

• RNAseq data from NEN patient derived tumor organoids (PDTOs) and matched parental tumors - MUMC

  The dataset includes fastq files from 4 NEN tumors or metastases and matched PDTOs. The sequencing was done with either a Nextseq 2000 or a NovaSeq 6000 instrument.

  Dataset EGAD00001009991

• RNAseq in ASD patients and controls

  RNA sequences of a total of 24 samples, including 13 unrelated ASD patients (13 males) and 11 adult individuals of Spanish origin as controls (4 males, 7 females). The RNAseq study was conducted on a HiSeq 4000 (Illumina) and paired-end sequences were obtained (fastq files).

  Dataset EGAD00001008160

• Genome sequence data from a metastatic paraganglioma patient

  Genome sequence data from a metastatic paraganglioma patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001010985

• Cancer Genomics of the Kidney

  The aim of CAGEKID is to carry out comprehensive detection of DNA markers for conventional (clear cell) renal carcinoma. The project includes complete analysis of somatic and constitutional DNA variation, methylation patterns and expression in a large number of constitutional/tumor pairs. CAGEKID is a part of the International Cancer Genome Consortium, ICGC.

  Dataset EGAD00001004018

• Metastases of a cancer of unknown primary (CUP)

  Dac EGAC00001001484

• Precision Medicine for ABCA4 Disease: Modifier Alleles

  Genetic variation affecting the structure and function of the ABCA4 protein gives rise to a broad collection of genetically and clinically heterogeneous diseases, collectively known as ABCA4 disease, which are characterized by both phenotypic overlap and variable penetrance and expressivity. These include autosomal recessive Stargardt disease, cone-rod dystrophy, occult maculopathy, bull's eye macular dystrophy, retinitis pigmentosa-like retinal dystrophy, etc. Some phenotypic variation can be attributed to variability of highly penetrant ABCA4 mutations; however, much of the heterogeneity cannot be explained by ABCA4 mutations alone. The concept of Precision Medicine requires, by definition, identification of all genetic variation contributing to specific disease phenotypes. The main goal of this study is to identify all genetic variation resulting in phenotypes compatible with ABCA4 disease, which, in addition to biallelic disease-causing variants in the ABCA4 locus, include cis- and trans-acting modifiers and mutations in genes other than ABCA4.The study was carried out by performing whole exome sequencing (WES) of affected individuals to identify causal and modifying genetic variation for patients with macular dystrophies compatible with ABCA4 disease. All samples were sequenced with the IDT's Exome Research Panel Version 1 with SeqCap EZ Exome v2 and SeqCap EZ Exome v3 capture kits. Samples were sequenced on Illumina next-generation sequencing machines (San Diego, CA, USA) using DRAGEN Bio-IT Platform v. 2.5.1 (Illumina) to align reads to the Genome Reference Consortium Human Build 37, calling variants in accordance with the Genome Analysis Tool Kit (GATK, v.4.0.2.1) Best Practices Workflow, using ATAV (v.7.0.16) variant-calling pipeline. Variants for analysis were restricted to the consensus coding sequencing public transcripts (CCDS release 20) plus 2 base pair (bp) intronic extensions. Variants were annotated using ClinEff (DnaMiner) with Ensembl-HGRCh37.73 annotations.This set of WES data from unrelated patients of different racial and ethnic backgrounds can be stored and shared through dbGaP. These data provide information on frequencies of disease-causing variants in genes other than ABCA4 in patients with macular dystrophies. These also provide frequencies of selected pathogenic and none-pathogenic variants in different ethnicities.

  Study phs002393

• Genome-Wide Predictors of Treatment-Related Toxicities in SWOG S0221 Trial

  When undergoing treatment for breast cancer, many women experience severe side effects, some of which result in treatment-related death and some that can persist for years. Little is understood regarding factors that may predict drug toxicities. Pharmacogenetics, the investigation of variants in candidate genes in drug metabolism pathways, has been used to determine susceptibility to treatment-related toxicities, as well as to cancer recurrence. Although there have been some strong and important findings using this approach, such as identification of single nucleotide polymorphisms (SNPs) that predispose to side effects associated with thiopurines and irinotecan, there has been less progress in assessment of genetic variants that predispose to toxicities resulting from the multi-drug regimen commonly used to treat breast cancer, anthracyclines (A), cyclophosphamide (C), and taxanes (T). These difficulties in identification of key gene variants may be due to the complex metabolic pathways of these drugs, the lack of rate limiting enzymes in the processes, or the limitations of single SNP analysis, rather than capturing all of the variability across the genes. In addition to drug metabolism pathways, however, there may be a number of constitutional factors or other processes that affect damage to normal tissues in the course of chemotherapy, some known or hypothesized, such as DNA repair and oxidative stress pathways, and others not yet discovered. However, there have been no clear candidate genes that account for a large part of the variation in drug or treatment response, and there are likely important genes that influence sensitivity of cells to chemotherapy through unknown pathways which have not yet been identified or hypothesized. The present technological capabilities to screen the entire genome for variants that discriminate populations allows the opportunity to identify these as yet unknown pathways, and open the doors to exciting new avenues of research into mechanisms that had not been previously considered. We conducted a genome-wide scan (GWAS) in a clinical trial (S0221), in which women with high risk breast cancer were treated with different dosing schedules of C, A and T. Blood specimens were collected and banked, and DNA extracted for genotyping on the Illumina OMNI 1M platform. The GWAS data were used to examine genetic variants significantly associated with grades 3 and 4 toxicities, including peripheral neuropathy recorded during the T segment. In S0221, toxicities were graded according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE). The neurotoxicity is predominantly a distal sensory neuropathy, which is characterized by pain, numbness, tingling, and reduced functional capacity in the extremities. Other symptoms include parasthesias, ataxia, impaired vibration and joint position sense, and loss of tendon reflexes. By using a GWAS approach, it is likely that important pathways not previously considered can be revealed as important in susceptibility to treatment-related toxicities, identifying those at greatest risk for alternate drugs or dose reduction, and opening new areas of research for prevention of taxanes-related neuropathy among patients receiving chemotherapy for breast cancer.

  Study phs001428

• Smith-Lemli-Opitz Syndrome: A Longitudinal Clinical Study of Patients Receiving Cholesterol Supplementation

  Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol production by the body. It is caused by changes in the DHCR7 gene, which is the blueprint for an enzyme called 7-dehydrocholesterol- delta7-reductase. This enzyme is necessary for the production of cholesterol by all cells in the body. People with SLOS often have malformations of major organs, slow growth, feeding difficulties and intellectual disability or learning problems. Because patients with SLOS cannot make enough cholesterol, it has been proposed that cholesterol supplementation (either with egg yolk or liquid suspensions of cholesterol) could help improve the symptoms of the disease. However, despite the widespread use of cholesterol supplementation, it is still not known whether it works or not. The study will try to provide an answer to this question by studying the disease and its progression while patients are receiving cholesterol. The clinical features of SLOS are thought to be related to low cholesterol and buildup of toxic cholesterol precursors (substances from which cholesterol is formed). But how exactly low cholesterol and toxic precursors contribute to the disease is poorly understood. This knowledge is critically important because it should help discover new therapeutic targets and develop treatments of the disease in the long run. The study will try to fill this gap with a comprehensive clinical and biochemical testing of the study participants over the course of several years. Last, a limitation of previous SLOS research studies has been their low number of participants. This is understandable because SLOS is a rare diseases and few research groups are working on it. However, in order to fully understand the disease, researchers need to study as many patients as possible. This study is unique in that it is run by a network of several highly specialized clinical research sites across the country. Having several sites involved increases the researcher's ability to recruit and study large number of patients, and centralize patients' information in a comprehensive SLOS clinical registry. This registry will be key to identify markers for diagnostic testing, screening and measuring outcomes in future studies of treatment. The purpose of this study is to learn as much as possible about Smith-Lemli-Opitz Syndrome (SLOS) by following a large group of affected children and adults over time. In this study, we will measure cholesterol and other similar chemicals in blood and urine, evaluate development and behavior, do limited medical evaluation, and carry out brain imaging studies.This study will help researchers: learn more about what causes SLOS and how SLOS changes with age, note differences in features of SLOS among those affected, evaluate the effect of giving extra cholesterol in this condition, and develop ways to evaluate whether treatments developed in the future will be helpful.

  Study phs001430

• Disorders/Differences of Sex Development (DSD) Study Performed at UCLA in Collaboration with the DSD-Translational Research Network (DSD-TRN), with the Support of the Gabriella Miller Kids First Pediatric Research Program

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. Whole Genome Sequence (WGS) and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Disorders/Differences of Sex Development (DSD) are congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical. DSD are chronic medical conditions collectively affecting ~1% of the population, frequently requiring life-long care by multiple specialists, and carrying a significant public health burden. Some are associated with life-threatening events, such as adrenal crises in Congenital Adrenal Hyperplasia (CAH). DSD are also associated with increased infertility, cancer, gender dysphoria risks, psychosocial distress and pervasive challenges to health-related quality of life (HRQoL) for patients and families. DSD are broadly classified into three categories: sex chromosome DSD, 46,XY DSD and 46,XX DSD, and further classified according to the type of gonad found in the patient (ovary, testis, ovotestis). We were able to increase significantly the diagnostic success for DSD using Whole Exome Sequencing (WES), with the identification of disease-causing and likely pathogenic variants in a third of a cohort of 46,XY patients. We have therefore proposed a shift in the diagnostic approach to DSD to use next-gen sequencing as a first-line clinical test, which could lead to faster and more accurate diagnosis, and orient further clinical management, limiting unnecessary, costly, and often invasive endocrine testing and imaging. However many remain unexplained (over half of the XY cases, a significant minority of XX cases, including most ovotesticular DSD, and most syndromic cases). In addition, the very large phenotypic variability in cases with known variants in the same gene is unexplained. We here propose to use Whole-Genome Sequencing (WGS), which dramatically improves upon exome sequencing, covering both coding and non-coding parts of the genome more uniformly, as an approach to not only improve diagnostic yield, but also to identify novel genes and regulatory elements involved in DSD.

  Study phs001178

• TOPDECC-Trans-omics for Precision Dentistry and Early Childhood Caries: Genome-Wide Genotyping (CIDR) and Microbiome in the ZOE 2.0 Study

  The ZOE 2.0 study is a cross-sectional genetic epidemiologic investigation of early childhood oral health, conducted in a state-wide, community-based, multi-ethnic sample of 3-5-year-old preschool-age children in North Carolina, United States. Between 2016-2019, 8,059 children were enrolled and 6,404 of them underwent comprehensive oral-clinical examinations that provided usable data on dental caries (i.e., early childhood caries; ECC) phenotypes. Saliva samples and supragingival biofilm samples were collected by 10 trained and calibrated examiners during the clinical encounters that took place in enrolled children's preschool (Head Start) centers. Specifically, the study enrolled participants and conducted clinical examinations in 260 Head Start centers that belonged to 34 Head Start programs in NC. 6,262 participants provided clinical data and had extracted DNA that met quantity and quality criteria for high-density genotyping and 6,144 of them were retained in the genome-wide association study (GWAS). Additional information on oral health-related behaviors, risk factors and self-reported outcomes was collected prior to the conduct of the clinical exam using self-administered questionnaires completed by children's guardians. Height and weight measurements were used to derive measures of adiposity. A domestic water sample for fluoride concentration measurement was obtained after the clinical examination for approximately 25% of study participants, to provide a measure of environmental exposure to this known caries-preventive agent and this information was subsequently imputed to the entire cohort using a novel GIS-informed method. Supragingival biofilm samples for microbiome analyses were collected from all participating children. Biofilm samples from a pilot 5% (n=300) of the cohort were carried forward to WGS (metagenomics; MTG) and RNAseq (metatranscriptomics; MTX) analyses, and these sequence data are being released via the Sequence Read Archive (SRA) in this dbGaP accession: 300 participants with MTG, 297 of those with MTX. Of note, the 17 participants with MTG data did not have genotypes produced, therefore the study's released participant total count is 6161, including 6144 (with genotypes released) plus 17 (with no genotypes released but with MTG data in the SRA).The study's primary objective is to identify risk loci and gene sets/pathways for ECC and related traits (e.g., caries prevalence and severity) by conducting a trans-ethnic GWAS. Genotyping is based on the Infinium™ Global Diversity Array and the TOPMed panel is used for imputation via the University of Michigan Imputation server. Secondarily, the ZOE 2.0 seeks to determine prevalence and severity of dental caries, other oral disease outcomes, and putative risk factors for dental caries in this low-income population-based sample of European-, African-, and Hispanic/Latino-American preschool-age children.

  Study phs002232

• International Standards for Cytogenomic Arrays

  The International Standards for Cytogenomic Arrays (ISCA) Consortium is a rapidly growing group of clinical cytogenetics and molecular genetics laboratories committed to improving quality of patient care related to clinical genetic testing using new molecular cytogenetic technologies including array comparative genomic hybridization (aCGH) and quantitative SNP analysis by microarrays or bead chip technology. The ISCA Consortium is now working with the sequencing community to extend the goals of standardization, collaboration, and data sharing. To reflect this combined effort, we are becoming ICCG, or the International Collaboration for Clinical Genomics. Efforts of the Consortium include: Clinical Utility: The ISCA Consortium has made recommendations regarding the appropriate clinical indications for cytogenetic array testing (Miller et al. AJHG 2010, PMID: 20466091). Currently, discussions are focused on pediatric applications for children with unexplained developmental delay, intellectual disability, autism and other developmental disabilities. A separate committee has been developed to address appropriate cancer genetic applications (http://www.urmc.rochester.edu/ccmc/). Evidence-based standards for cytogenomic array design: The Consortium will develop recommendations for standards for the design, resolution and content of cytogenomic arrays using an evidence-based process and an international panel of experts in clinical genetics, clinical laboratory genetics (cytogenetics and molecular genetics), genomics and bioinformatics. This design is intended to be platform and vendor-neutral (common denominator is genome sequence coordinates), and is a dynamic process with input from the broader genetics community and evidence-based review by the expert panel (a Steering Committee with international representation). Public Database for clinical and research community: It is essential that a publicly available database be created and maintained for cytogenetic array data generated in clinical testing laboratories. This will be integrated into the current dbGaP database at NCBI/NIH and released through dbVar, and curated by a committee of clinical genetics laboratory experts. The very high quality of copy number data (i.e., deletions and duplications) coming from clinical laboratories combined with expert curation will produce an invaluable resource to the clinical and research communities. Standards for interpretation of cytogenetic array results: Using the ISCA Database, along with other genomic and genetics databases, the Consortium will develop recommendations for the interpretation and reporting of pathogenic vs. benign copy number changes as well as imbalances of uncertain clinical significance. Membership in the ISCA Consortium is open to all individuals and laboratories involved in cytogenetic array testing who are committed to free data sharing and to participation in a process to develop evidence-based standards and guidelines to improve patient care. ISCA is available through dbVar: http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd37/ http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd75/ http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd45/ http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd101/

  Study phs000205

• Birth Defects: Moebius Syndrome and Related Congenital Facial Weakness Disorders

  It is estimated that about 1 in every 33 infants in the United States is born with a birth defect. Among these, the subset of birth defect syndromes associated with facial weakness and lack of facial expression can have profound implications for social interactions and psychosocial development. Moebius syndrome is defined by congenital and non-progressive facial weakness and limited eye abduction, and most cases are believed to result from dysfunction of cranial nuclei/nerves VI and VII. Although rare, this syndrome causes significant impairment because of facial weakness and associated intellectual disabilities, autism, hearing loss, difficulty swallowing and breathing, peripheral neuropathy, muscle hypotonia, heart defects, chest wall abnormalities, and limb malformations. The phenotypic spectrum and the associated genetic and environmental factors underlying Moebius syndrome are poorly understood. The goal of this research is to identify causative gene mutations for Moebius syndrome and related conditions, such as Moebius-Poland or -Robin sequence, hereditary congenital facial paresis (HCFP), and oculoauriculovertebral dysplasia (Goldenhar syndrome). This proposal builds on an ongoing collaboration among researchers at Mount Sinai Medical Center, Boston Children's Hospital, NHGRI intramural program, and the Moebius Syndrome Foundation, but aims to greatly extend that work by collaboration with investigators in the NIH Clinical Center (CC). Our groups have already defined a new autosomal dominant syndrome with Moebius syndrome, Kallmann syndrome, cyclic vomiting resulting from a TUBB3 E410K substitution. We have also identified a new autosomal recessive Moebius-related syndrome with bilateral facial palsy, hearing loss, and strabismus resulting from a HOXB1 R207C substitution. Through collaborative efforts of these extramural teams with intramural investigators, whole exome sequencing (WES) has been conducted for four families with Moebius-like features, and data analyses are ongoing. The overall goal of this new grant application will be to conduct extensive phenotype analysis on approximately 24 families per year with Moebius and other undefined syndromes with facial weakness. Studies to be conducted at the CC include neurology, psychiatry, neurocognitive, rehabilitation medicine (muscle strength, speech/language pathology), ophthalmology, audiology, and genetics evaluations; autism screening; electromyography, nerve conduction, and blink reflex studies; videoscopy of quantitative eye movement recordings; 3D-CT craniofacial imaging; MRI of the brain, orbit, internal auditory canals, posterior fossa including brain diffusion tensor imaging for tractography; and genetic counseling. Jointly with the extramural teams, WES analysis and variant confirmation will be performed. A more comprehensive definition of the phenotypic and genotypic spectrum of these birth defects will have a significant impact on our understanding of the molecular pathways underlying dysmorphologies, cranial nerve development, and more common childhood disorders such as autism. Thus, this project will lead to strategies for prevention and treatment of birth defects.

  Study phs001383

• Multi-Modal Single-Cell, Spatial, and Genomic Analyses of Human Non-Small Cell Lung Cancer Brain Metastases

  We performed single nuclei RNA-sequencing (snRNA-seq) with matched T cell receptor sequencing (TCR-seq), and pool matched low pass whole genome sequencing (WGS) of 12 treatment-naive non-small cell lung cancer (NSCLC) primary tumors (PTs) and 31 treatment-naive NSCLC brain metastases (BMs). In total, we recovered 277,206 cell transcriptomes in 43 samples. Single-nuclei suspension from frozen NSCLC metastases were generated using methods published in Slyper et al. (Nature Medicine, 2020, PMID:32405060) with modifications. The tissue was first cut in 20 µm sections using a cryostat and stored on dry ice until the next step. Then the tissue was put on wet ice and washed once with 5 ml PBS to remove OCT. After this step nuclei were extracted by vigorous pipetting in salt-tris buffer with Tween-20 (TST) followed by a high-volume wash in salt-tris buffer (ST). Nuclei were counted and 10,000-14,000 and were loaded using a Chromium controller (10X genomics) and Chromium Single Cell 5' Reagents (V1.1 and V2). Complementary DNA libraries were generated according to manufacturer's instructions, with the modification of one additional cycle of amplification. Matched single nuclei T cell receptor (snTCR) sequencing libraries were prepared from amplified cDNA libraries using either Chromium Single Cell V(D)J Enrichment Kit for human T cells Reagent Kit, v1.1, or single cell human TCR amplification kit. Final snTCR sequencing libraries were prepared using Single Index Kit T Set A for V1.1 libraries or Library construction kit and Dual Index Kit TT set A for V2 libraries. Sequencing libraries were quantified using Tapestation D5000 reagents and a 2200 TapeStation and pooled for sequencing. Pool matched low pass whole-genome sequencing (lp-WGS) was performed in addition to snRNA-seq to improve the identification of the malignant and non-malignant cell compartments. Nuclei from snRNA-seq sample preparations were collected by centrifugation (500g, 5 min), snap frozen after removing excess ST buffer, and stored at -200C until further processing. If insufficient nuclei (0C for 9 minutes. Adapters were not diluted, and the optional PCR (5 cycles) and cleanup were performed. After library cleanup with AMPure beads (Beckman Coulter, Brea, CA), libraries were quantified with Tapestation D5000 HS tapes (Agilent) and stored at -200C until sequencing.Using multiplexed immunofluorescence in an independent cohort of treatment-naïve pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features that strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.

  Study phs003865

• PE-CGS: Optimizing Engagement of Hispanic Colorectal Cancer Patients in Cancer Genomic Characterization Studies

  Colorectal Cancer (CRC) is the second leading cause of cancer death in the US. Hispanic/Latinos (H/L) are the largest and fasting growing ethnic group in the US, and cancer is the leading cause of death among H/L in the US. Therefore, we need to fully understand the full complexity of the molecular etiology of cancer in this ethnic group. For instance, although incidence rates of CRC are lower among Latinos as compared to Whites or African Americans, Hispanics with metastatic disease have shorter overall survival when adjusted for health care setting, demographics, disease characteristics and treatment factors. H/L also tend to be diagnosed at a younger age and with higher stage, and we have previously reported that Mexican H/L in California have the greatest proportion of young (The Cancer Genome Atlas has provided a deep overview of the molecular taxonomy of CRC in 594 cases, however, less than 1% of the cases (n=5) were H/L. Therefore, it is imperative for us to take more detailed assessment of the molecular genomic landscape of CRC in H/L. One of the major issues likely limiting our ability to perform these large genomic initiatives in minority patients is that Patient or Participant Engagement practices may not be investigated to identify best practices for accruing and consenting patients into clinical translational biomedical research studies. This concept of Participant Engagement is critically important for both the patients and the translational cancer research community. Optimizing and improving our approaches for directly engaging patients at initial contact, throughout the course of a translational genomic study, and during the time of return of results is likely to lead to stronger relationships between the medical community and patients, but could also lead to significant improvement in outcomes for patients and for the cancer care community as a whole. As such, we propose the creation of the USC Center for Optimization of Participant Engagement in Cancer Characterization (COPECC) with a focus on optimizing the engagement of Latinos in CRC Genomic Characterization research studies. USC COPECC would serve as a member of the NCI U2C Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Our investigative team includes experts in all relevant areas of research for genomic characterization, participant engagement, and engagement optimization. We have an established platform for consenting patients into cancer genomics studies that will serve as a standard process. The overall goal of USC COPECC is to generate results on participant engagement optimization and CRC genomic research that will be shared with the broader community to distribute best practices for engaging Latinos in hopes of improving overall outcomes for CRC in this underserved population.

  Study phs003985

• Characterization of Structural Variants in Acute Myeloid Leukemia Patients

  Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and is expected to increase in frequency as the population ages. Most subtypes of AML are difficult to treat, in part due to a lack of understanding of possible molecular targets. Furthermore, the peak incidence of AML is in the sixth decade, and patients over the age of 65 do not tolerate chemotherapeutic regimens well. Moreover, AML has been highly studied as a model for other cancers. An RNA Biology Program is established aiming to develop comprehensive datasets through the profiling of all different classes of RNA expression, RNA editing, alternative splicing, and non-coding RNAs in CD34+ normal hematopoietic stem cells (HSC), their differentiated progeny, and AML clinical samples that could be utilized to understand leukemia. These datasets will allow us to computationally identify and characterize various RNA species and processes to enable the development of effective therapeutics to AML, leukemia and other types of cancers. Epigenetic factors such as methylation and histone modifications will also be characterized from these clinical samples allowing for integrated dataset analysis to look at the cross-talk between RNA and DNA/epigenomics in leukemia. The following is a subsidiary study of the above study description where whole genome sequencing was performed on two collected AML patients' samples using Illumina and Oxford Nanopore sequencing technologies. The aim is to characterize the roles of structural variants (SV) in RNA biology which are potentially important for AML development using our own established long-read SV characterization tool, NanoVar. The advent of Oxford Nanopore sequencing technologies has opened a new avenue for better SV characterization by having longer sequencing reads. NanoVar is an accurate and rapid SV characterization tool that utilizes low-depth Nanopore sequencing data. NanoVar makes use of split-reads and hard-clipped reads for SV discovery and employs a simulation-trained neural network classifier for true positive enrichment. NanoVar exhibited higher accuracy and faster computational speed amongst other long-read SV detection tools in simulated data. In AML patient data, NanoVar displayed excellent accuracy in SV characterization (16/16 SVs validated in two patients) by using only 4x depth sequencing data. In summary, NanoVar improves the accuracy and speed of SV characterization at a lower sequencing cost, an approach compatible with clinical studies.

  Study phs001847

• UK10K RARE COLOBOMA

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. Ocular coloboma is the most common significant developmental eye defect with an incidence of ~1 in 5,000 live births. It results from failure of optic fissure closure during embryogenesis. The position and extent of the fusion failure dictates the clinical appearance and functional effect. ~30% of coloboma cases are associated with other systemic malformations. These UK10K samples will mostly comprise isolated coloboma cases without systemic involvement (aka non-syndromal coloboma). There is strong evidence from family studies that coloboma has a major genetic component with autosomal dominance being the most common pattern of inheritance. However, many cases are isolated or show complex patterns of familial clustering. The genes responsible for isolated coloboma are largely unknown, but in a small number of families mutations in SHH, CHX10, and PAX6 have been identified indicating marked genetic heterogeneity. Thus in addition to the clinical benefits of achieving a molecular diagnosis there are also major scientific advantages to identifying coloboma genes, as these are likely to provide insights into the complex process of optic fissure closure, that is critical to normal eye development. In the longer term, understanding the molecular basis of the disease may provide clues to therapeutic strategies.For further information with regard to this cohort please contact David Fitzpatrick (david.fitzpatrick@ed.ac.uk).

  Study EGAS00001000127

• UK10K_OBESITY_SCOOP

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.The SCOOP samples are part of the Obesity group and will undergo exome sequencing. Severe Childhood Onset Obesity Project (SCOOP) is a sub-cohort of the Genetics Of Obesity Study (GOOS) cohort established by Sadaf Farooqi and Steve O’Rahilly at the University of Cambridge over the last 12 years. The GOOS cohort contains >4,000 patients of diverse geographic origin, many of whom have monogenic and syndromic forms of obesity, and includes patients that are offspring of consanguineous union. SCOOP is a subset of >1500 UK Caucasian patients with severe, early onset obesity (all patients have a BMI Standard Deviation Score (SDS) > 3 and obesity onset before the age of 10 years), in whom all known monogenic causes of obesity have been excluded. GWAS data on the SCOOP cohort will be available (WTCCC2 independent study) at the time of the start of this study. Data from this cohort has demonstrated that the prevalence of the common obesity risk alleles in FTO, MC4R and NEGR1 are amongst the highest within SCOOP, demonstrating its value also in the study of genetic variants with an impact on more common obesity. For further information with regard to this cohort please contact Sadaf Farooqi (isf20@medschl.cam.ac.uk).

  Study EGAS00001000124

• HLA-A*3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans

  Based on the prior knowledge of involvement of the human leukocyte antigen locus in Han Chinese patients with carbamazepine-induced Stevens-Johnson syndrome, we imputed the HLA types for each case and control subject from the array of SNPs in the Human610-Quad GWAS platform (NCBI Build 36.1). We then performed a genome-wide association test which included the imputed HLA alleles as markers.

  Study EGAS00000000036

• Cell-Free DNA Genomic Profiling and its Clinical Implementation in Advanced Prostate Cancer

  Sixty-eight patients with advanced prostate cancer in castration-resistant or castration-sensitive settings undergoing treatment at the University Hospital Basel or the St. Claraspital Basel (Switzerland) were selected for targeted parallel sequencing analysis on liquid biopsy (plasma cfDNA) and matched formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples. The liquid biopsy sequencing (plasma cfDNA) was performed using a custom-designed targeted AmpliSeq HD Prostate Cancer cfDNA panel on all 68 patients. The sequencing on 42 matched FFPE tumor biopsy samples was performed using a custom-designed or an alternative commercial panel (ThermoFisher). Raw data underwent automated processing on the Ion Torrent Server v5.16.1 (ThermoFIsher) and were aligned to a hg19 reference genome using the Torrent Alignment Software (ThermoFihser).

  Dataset EGAD50000000348

• A Genome-Wide Association Study of CALGB 90401: Randomized, Double-Blind, Placebo-Controlled Phase III Trial Comparing Docetaxel and Prednisone with or without Bevacizumab in Men with Metastatic Castration-Resistant Prostate Cancer

  The Cancer and Leukemia Group B (CALGB) 90401 trial compared docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer. A genome-wide association study using clinical outcomes and toxicities was conducted on the basis of data from CALGB patients who provided consent for pharmacogenomic studies and usable DNA

  Study phs001002

• A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity

  We identified a gradated transcriptional program of coordinately regulated inflammation-suppressive genes in psoriatic resident memory T cells. This dataset includes bulk RNA-seq for CRISPR-based deactivation of two core components of this inflammation-suppressive program, ZFP36L2 and ZFP36, in human PBMCs. It also includes scRNA-seq of cutaneous immune cells from psoriasis patients before and during therapeutic IL-23 blockade.

  Study EGAS00001006716

• GEX CITE-Seq performance dataset

  To understand the impact of enzymatic treatments on gene expression and epitope preservation on major immune cell populations, skin dissociation (SkinD) and solid soft tumor dissociation (TumorD) were tested on three healthy PBMC samples in triplicate (D1, D2, D3), against an untreated control. CITE-seq performance was assessed on a solid biopsy cohort of 11 samples (5 healthy skin samples, 3 primary melanoma samples, 3 melanoma metastasis samples) as well as on a liquid biopsy PBMC cohort consisting of three healthy donors and three immunotherapy-treated melanoma patients. This dataset contains the GEX data for each sample. Data is provided in the form of pooled BAM files. Linkage between samples, BAM files and hashtags is provided in a separate linkage file.

  Dataset EGAD00001008418

• ADT/SPEX CITE-Seq performance dataset

  To understand the impact of enzymatic treatments on gene expression and epitope preservation on major immune cell populations, skin dissociation (SkinD) and solid soft tumor dissociation (TumorD) were tested on three healthy PBMC samples in triplicate (D1, D2, D3), against an untreated control. CITE-seq performance was assessed on a solid biopsy cohort of 11 samples (5 healthy skin samples, 3 primary melanoma samples, 3 melanoma metastasis samples) as well as on a liquid biopsy PBMC cohort consisting of three healthy donors and three immunotherapy-treated melanoma patients. This dataset contains the ADT/SPEX data for each sample. Data is provided in the form of pooled BAM files. Linkage between samples, BAM files and hashtags is provided in a separate linkage file.

  Dataset EGAD00001008419