Search Results - EGA European Genome-Phenome Archive

The most common and well-known causes of diabetes are type 1 and type 2 diabetes; however, there are many other etiologies of diabetes. At least 1-2% of diabetes cases result from high penetrance single gene defects, most commonly in a gene encoding either a transcription factor involved in beta cell development and function or the enzyme glucokinase (GCK). Others have mutations in transcription factors necessary for beta cell development and function. This subset of monogenic diabetes cases is autosomal dominant and is known as "Maturity-Onset Diabetes of the Young" (MODY). Patients with type 1 diabetes are insulin dependent, meaning they lack insulin production and therefore require multiple daily injections of insulin, as well as multiple times a day blood glucose monitoring. This can be quite burdensome. Type 2 diabetes is predominantly an insulin resistance problem and can often be managed with pills initially, but there are many who also require insulin either at diagnosis or later on in their disease course. Usually, monogenic diabetes is misdiagnosed as type 1 or type 2 diabetes and thus treated suboptimally. Those with monogenic diabetes, due to a defect in a gene encoding a transcription factor, respond extremely well to a class of oral diabetes medications called sulfonylureas. Those with GCK-MODY often have a mild, stable, fasting, nonprogressive hyperglycemia for which pharmacological treatment is often not necessary. It is important to accurately diagnose our patients with the correct etiology to their diabetes for a multitude of reasons. Accurately diagnosing a patient with MODY, for example, can predict their clinical course and we can tailor treatment accordingly. If diagnosed with a transcription factor MODY, we can try switching the patient from insulin to an oral sulfonylurea, and if diagnosed with a GCK-MODY, we can consider discontinuing pharmacological treatment altogether. With specific tailoring of treatment, we would hope to improve quality of life by discontinuing perhaps multiple daily injections of insulin and glucose checking as these may not be necessary. In addition, we would hope to improve glycemic control with an eventual decreased cost to society by decreasing the complication rate of diabetes, resulting in less specialty referrals, lab tests, supplies and procedures. Further, given MODY is an autosomal dominant condition with a 50% chance of inheritance to first-degree family members, we could offer testing to asymptomatic family members which could lead to prevention and/or early diagnosis and treatment. Overall, testing for monogenic diabetes is underutilized clinically. Testing is being done in the U.K., but in the U.S. we are lagging behind. This is most predominantly due to lack of knowledge and concern over cost. In addition, it is difficult to differentiate the relatively small number of monogenic diabetes cases from the larger number with type 1 and type 2 diabetes as each of these etiologies have overlapping characteristics. In fact, many patients with monogenic diabetes are being misdiagnosed with type 1 and type 2 diabetes. There are recommendations set forth by different societies on who to consider screening for monogenic diabetes. However, these recommendations are difficult to employ clinically as they are general recommendations, there is no specific algorithm, and they are based on varying levels of evidence. The purpose of this study is to implement a personalized diabetes medicine program to enhance the identification of individuals and families affected by highly penetrant diabetes gene mutations through a combination of systematic screening and genetic testing at the University of Maryland Center for Diabetes and Endocrinology, the Baltimore VA Medical Center and additional partner centers at Geisinger Health System and Bay West Endocrinology Associates, and other UM outpatient clinics. Our hope is to develop an approach that can be eventually implemented across the United States so that we can more often uncover the correct etiology to diabetes, tailor treatment accordingly, and test asymptomatic family members.

Study phs001771

Phase II Therapeutic Trial of Mexiletine in Non-Dystrophic Myotonia (IND #77,021)

Non-dystrophic myotonias are a group of rare muscle disorders caused by abnormalities in different muscle cell membrane proteins. Patients experience delayed muscle relaxation that causes impaired physical activity, stiffness, and pain. Mexiletine has been shown to be beneficial for symptoms of myotonia in case reports of patients with non-dystrophic myotonia, however, current management of these patients primarily depends on individual practitioners' preference. This study is a placebo-controlled, double-blind, cross-over treatment trial using mexiletine in non-dystrophic myotonias. The results, if positive, will permit the identification of mexiletine as an effective therapy for myotonia, making it a first-line therapy for patients with non-dystrophic myotonia. The specific aim of this proposal is to perform a randomized, double-blind, placebo-controlled cross-over study to assess whether mexiletine improves both quantitative and qualitative measures of myotonia in patients with non-dystrophic myotonia. Given the rarity of non-dystrophic myotonia, large randomized controlled treatment trials in these disorders have not been feasible in the past. Primary Outcome Measure: Patient-assessed symptom: stiffness as measured by an Interactive Voice Response Diary (IVR). Secondary Outcome Measures: a) patient-assessed pain, weakness, and fatigue as measured by IVR; b) clinical myotonia assessment; c) quality of life as measured by INQoL, SF36; d) a quantitative measure of grip myotonia; e) measurement of CMAP after short and long exercise; f) grading of myotonia on needle EMG.

Study phs001311

National Cancer Institute (NCI) Genome-Wide Association Study (GWAS) of Renal Cell Carcinoma in African Americans

The NCI GWAS of renal cell carcinoma (RCC) in African Americans was undertaken to provide insight into genetic loci affecting susceptibility to this malignancy in a racial group known to be at elevated risk. We genotyped 1,136,723 single-nucleotide polymorphisms (SNPs) among 255 cases and 375 controls of African ancestry from the NCI Kidney Cancer Study, and further investigated 16 SNPs in a replication set consisting of 140 cases and 543 controls from a case-control study conducted at the University of Texas MD Anderson Cancer Center. The variant rs10771279 located on 12p11, 77kb from a European-ancestry RCC risk marker, was associated with RCC risk in the GWAS (P=1.2 x 10-7) but did not replicate (P=0.99). The variant 7105934 on 11q13.3, previously associated with RCC in a GWAS using European-ancestry samples, was associated with risk in both studies [meta-analysis odds ratio (OR)=0.76, 95% confidence interval (CI)=0.64-0.91; P=0.0022]. The frequency of this allele was higher than that observed in the European-ancestry GWAS (0.56 and 0.07 respectively among controls). The rs7105934 association was stronger for clear cell RCC (ccRCC: OR=0.56; P=7.4 x 10-7) and absent for cases of other or unknown histology (OR=1.02; P=0.86). In conclusion, this study provides evidence that rs7105934 is a susceptibility locus for RCC, and clear-cell RCC in particular, among African Americans.

Study phs000863

NINDS Family-Based Whole-Genome Sequencing to Find Modifiers of Age of Onset in Huntington's Disease

The goal of our studies is to identify genetic modifiers of neurodegeneration in Huntington's disease (HD). HD is caused by expansion of CAG repeats in the huntingtin (Htt) gene, with longer stretches often leading to more rapid disease onset and progression. Yet, for a given number of repeats, the age of symptom onset can be variable, differing by up to decades. Thus, the age of onset of motor symptoms in HD is only partly explained by the length of the CAG expansion. Available evidence suggests that genetic modifiers contribute to the variation in HD onset. Identifying genetic modifiers is important because they may provide critical insights into HD pathogenesis and reveal key pathways that could be targeted by novel HD therapeutics. This is important since there are no disease-modifying therapies for HD, and mHtt is an unattractive small-molecule drug target. We recruited 21 HD families with varying characteristics of disease progression and age of onset and obtained medical histories, clinical records and DNA samples that were subjected to whole-genome sequencing (WGS). These WGS data describe families of 104 subjects, including HD patients and their unaffected family members. These individuals were selected based on individual clinical histories and family structures that best fit our criteria for expressing potential genetic modifiers. We are testing the hypothesis that novel, rare genetic variants contribute to HD and those genetic modifiers can be identified by WGS.

Study phs001071

Male Infertility: Genetics of Spermatogenic Failure

Spermatogenesis is a complex biological process that requires the coordination of thousands of genes. Perhaps because of the large number of genes involved, spermatogenic failure occurs frequently and affects approximately 1% of men. While environmental and genetic factors likely contribute to this disorder, it is thought that the majority of cases have an underlying genetic basis. The two most common genetic causes are deletions on the Y chromosome and cytogenetic abnormalities (/e.g./ Klinefelter syndrome, XXY), which each account for roughly 10-15% of cases of complete spermatogenic failure. Point mutations in several other genes have also been linked to spermatogenic failure, but their collective prevalence is very low. Thus, for approximately 70% of men with spermatogenic failure, the genetic cause remains unknown. We hypothesize that a disproportionate number of these remaining genetic variants reside on the sex chromosomes because they are hemizygous in males and contain a disproportionate number of genes expressed in the testis. To identify genes that are required for spermatogenesis, we have performed capture-based targeted sequencing in 301 men with azoospermia (complete absence of sperm) and 300 fertile controls. Our sequencing is focused on coding genes and conserved, non-coding sequences of the X and Y chromosomes. In addition, we have targeted ~497 autosomal genes that display exclusive or predominant expression in the testis. The total sequence space targeted is 21.3 Mb, and we require >70% of targets reach an average coverage of 20X.

Study phs001023

Rare Cancer Tumors Project

A large proportion of common cancers affecting patients around the world have been selected for comprehensive cancer genome studies. Further efforts will be needed to tackle the remaining tumor types, including the rare forms of cancers. Although rare, these cancers tend to be more aggressive and fast growing with an early recurrence following initial chemotherapy and poor prognosis. Besides, patients diagnosed with rare cancers may have difficulty finding a physician knowledgeable in treating their type of cancer. While sample collection is a major challenge, the integrated genomic analyses would identify novel causative genes in these rare cancers, shed new light on the biology of the rare cancers, as well as guide novel targeted cancer therapies. Through efficient collaboration, the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine (BCM) has collected/is expected to collect 20 different types of rare cancers, 15-30 cases each. Whole-exome sequencing and high-resolution SNP array analysis were/will be performed for all cases and whole-genome sequencing was designed for a selected subset of the cases. The Rare Cancer Tumors Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in this sub-study, please click on the following sub-study below or in the "Sub-studies" section of this top-level study page phs000725 Rare Cancer Tumors Cohort. phs000754 Intracranial Germ Cell Tumors phs000861 Craniopharyngioma Tumors phs000859 Sezary Syndrome Genomic Analysis

Study phs000725

Detection and Targeting of Splicing Deregulation in Pediatric Acute Myeloid Leukemia Stem Cells

This study evaluates the gene expression and splicing changes between pediatric patients with and without Acute Myeloid Leukemia (AML) and pediatric and adult patients with AML. We obtained bone marrow or peripheral blood from patients and isolated CD34+ stem and/or progenitor cells from pediatric patients with AML (10) or without AML (6) and adult patients with AML (5). In parallel, a targeted analysis for known, deleterious, genetic mutations in the KRAS, NRAS, and KMT2C genes identified 2, 5, and 6 AML patients with alterations, respectively. Additionally, Tapestri analysis further identified a mutation in the intronic region of the SF3B1 gene in multiple pediatric AML patients. RNA-Seq was performed on the purified cell populations at The Scripps Research Institute Next Generation Core on an Illumina NextSeq 500 sequencer with 150bp paired-end reads.These datasets revealed that, similar to adult AML, pediatric AML samples were enriched for Leukemia Stem Cells (LSC) markers. A deeper analysis showed widespread dysregulation of splicing in pediatric AML samples compared to age-matched non-leukemic samples. In addition, the splicing regulator RBFOX2 was downregulated with an accompanying increase in specific CD47 splice isoforms in the pediatric AML samples. Thus, the increased presence of LSCs in pediatric AML is possibly driven by global splicing deregulation, and the treatment with splicing modulators like Rebecsinib has a potential therapeutic value for eradicating LSCs in these patients.

Study phs003196

Expression of Activation Induced Cytidine Deaminase and Risk of Transformation in Follicular Lymphoma

It is currently unclear how to identify follicular lymphoma (FL) patients with low disease burden but high risk for early progression. Building on a prior study demonstrating early transformation in FLs with high variant allele frequency (VAF) BCL2 mutations at activation-induced cytidine deaminase (AICDA) sites, we examined 11 AICDA mutational targets, including BCL2, BCL6, PAX5, PIM1, RHOH, SOCS1, and MYC, in a more contemporary cohort of 199 newly diagnosed grade 1 and grade 2 FLs using targeted capture and massively parallel sequencing. BCL2 mutations with VAF >20% occurred in 52% of cases. Among 97 FLs that did not initially receive rituximab-containing therapy, nonsynonymous BCL2 mutations at VAF >20% were associated with shorter, event-free survival (EFS, median 1.4 years with these mutations versus 4.5 years without, p = 0.048), and increased risk of transformation (HR 3.01, 95% CI 1.03-8.77, p = 0.04). Other sequenced genes were less frequently mutated and did not significantly increase the prognostic value of the panel. Across the entire population, BCL2 mutations at VAF >20% were associated with decreased EFS (HR 1.58, 95% CI 1.03-2.40, p = 0.034 after correction for FLIPI and treatment) and decreased overall survival after median 14-year follow-up (HR 1.86, 95% CI 1.07-3.23, p = 0.029). Thus, high VAF BCL2 mutations remain a prognostic factor for FL even in the chemoimmunotherapy era and might need to be considered in future study design.

Study phs002845

Whole Exome Sequencing of DNA from Pre-and Post-Chemotherapy Needle Biopsies of Triple Negative and Inflammatory Breast Cancers Enrolled in the S0800 Trial

Purpose: The purpose of this study was to assess the somatic mutation landscape of breast tumors before and after neoadjuvant chemotherapy. The data includes whole exome sequencing of pre- and post- tissues that were collected in the context of an already published clinical trial SWOG S0800 (ZA Nahleh et al. Breast Cancer Research and Treatment. 158:485-495, 2016). The trial compared the efficacy of sequential nab-paclitaxel followed or preceded by doxorubicin/cyclophosphamide anthracycline chemotherapy with or without bevacizumab as preoperative therapy for stage II-III breast cancer. Experimental Design: 29 pre-treatment biopsies and 9 matching post-treatment surgically resected cancer tissues were available for analysis and were subjected to whole exome sequencing to identify mutational patterns associated with response to neoadjuvant chemotherapy. The 9 paired samples with residual invasive cancer after therapy were also analyzed to assess changes in mutational patterns in response to therapy. No matching normal tissues were available for germline sequencing and therefore we used n=7 post-treatment breast tissues without residual cancer (i.e. complete eradication of cancer by therapy) as a normal cohort to facilitate somatic variant calling.Conclusion: These results suggest that genomic disturbances in BRCA-related DNA repair mechanisms, reflected by a dominant mutational signature 3, confer increased chemotherapy sensitivity. Cancers that survive neoadjuvant chemotherapy, frequently have alterations in cell cycle regulating genes but different genes are affected in different patients.

Study phs001883

Whole Genome Sequencing Analysis in a Family of Discordant Twins With Non-Syndromic Microtia and Hemifacial Microsomia: Identification of Novel Candidate Genes and Variants

This research is a non-NIH effort to discover the pathogenesis of non-syndromic microtia and to detect potential candidate genes. Microtia (OMIM 600674, 612290, 251800) is a spectrum of congenital anomalies and facial abnormalities, 90% of the cases followed by hearing loss. Two types of the disease are described in terms of connection to the affected syndromes: anomalies (syndromic) and only clinical manifestation (non-syndromic) associated with other symptoms. Though the exact pathogenesis of microtia remains unknown, pathogenic genes of majority of the microtia syndromic types have been identified. However, the genetic mutation of the non-syndromic microtia has not been confirmed. In this study, whole genome sequencing (WGS) was utilized to screen mutations in monozygotic discordant twins of congenital microtia-atresia and their family members. One of the twins, along with her grandfather, was discordant for microtia-atresia. By bioinformatic analysis of the WGS data from monozygotic twins with microtia and their non-microtia relatives, we proposed that among 28 identified potential genes, 4 of them (CNOT1, ODAD4, TBX15, and GIPC3) could be more responsible for non-syndromic microtia development and phenotypic features. Interested investigators may request to access the DNA genomic sequencing data of the study participants via dbGaP authorized access. In addition to raw genomic sequencing data, datasets of germline mutations and candidate gene mutations may also be available for investigators to request.

Study phs003216

Utility of Capillary Blood in Gene Expression Studies

The FAA Functional Genomics Team examined the feasibility of analyzing gene expression profiles using capillary blood collected by fingerstick, with the goal of developing practical fingerstick blood collections to expand blood collection capabilities and allow large-scale or field-based collections. We compared the RNA sequencing results obtained from two different capillary blood collection and RNA extraction methods with the results obtained from a standard venous blood collection and RNA extraction protocol. We also compared capillary blood processing methods, as well as fingerstick locations, within one capillary collection/extraction method. Within each method we sought to distinguish male from female participants to assess the capacity of each collection/extraction method for gene expression profiling. The study population included 40 participants aged 18-60 who were free from any acute illness or any illness that would preclude blood collection. We determined that capillary blood possesses large-scale significant differences from venous blood and that the two capillary methods produced similar gene expression profiles. We further determined that all methods were useful for detecting gene expression differences between assessed groups (male and female participants in this case). We conclude that capillary blood is suitable for gene expression profiling in quantities as low as 100 μL whole blood, but recommend that researchers should rely on a single blood collection method if they desire to compare results between individual studies. Raw sequencing files (.fastq) from this study are available in dbGaP.

Study phs003496

LCLF1.0 Data

In this study, we investigated ad libitum food intake of 20 healthy adult volunteers who each completed a 4-week stay at the National Institutes of Health (NIH). During their stay, they consumed a low-carbohydrate, high-fat (LCHF) diet and a low-fat, high-carbohydrate (LFHC) diet for 2 weeks each, in random order. We collected information about energy intake and metabolic changes in response to the two test diets. The test diets were presented to subjects in amounts exceeding their daily energy requirements, and subjects were instructed to eat as much or as little of each diet as desired. This study implemented 7-day rotating menus for each test diet. The diets were matched for presented calories and protein, but the LCHF diet was low in carbohydrate (~10% of calories) and high in fat (~75% of calories) whereas the LFHC diet was high in carbohydrates (~75% of calories) and low in fat (~10% of calories). The two test diets had a common foundation of vegetables with low amounts of digestible carbohydrates such as lettuce, spinach, kale, cabbage, cauliflower, zucchini, tomato, asparagus, broccoli, peppers, brussels sprouts, and green beans. The LCHF diet included meat, poultry, fish, eggs, dairy, and nuts. The LFHC diet included legumes, rice, root vegetables, soy products, corn, lentils, peas, whole grains, bread, and fruit. The test diets were designed using a standard computerized nutrition database, and blood samples were collected from the subjects.

Study phs003187

Esophageal Squamous Cell Carcinoma Precursor Study

Esophageal cancer is the sixth most common cause of cancer death in the world. High-risk areas occur across central Asia and from eastern to southern Africa, and in these populations, nearly all of the cases are esophageal squamous cell carcinoma (ESCC). ESCC has a dismal prognosis, largely because symptoms usually appear late in the course of the disease, when the tumors are incurable. Early detection and treatment of curable precursor lesions and early invasive ESCC in asymptomatic high-risk adults offers the potential for long-term survival and reduced mortality from this disease. Previous studies have shown that routine cytology of non-endoscopically collected esophageal cell samples is not sensitive and specific enough to be clinically useful, so we are now looking for molecular markers of high-grade esophageal squamous dysplasia (HGD), the proven clinically important precursor lesion of ESCC, that can be used to increase the accuracy and utility of this initial screening exam. National Cancer Institute (NCI) and Cancer Institute and Hospital, Chinese Academy of Medical Sciences (CAMS) began collaborative studies of ESCC since the mid-1980s in China. The present proposal is designed to characterize the type and prevalence of DNA mutations in tissue samples of HGD and to establish biologic and questionnaire resources for further study. The proposed study has two components, a field study to obtain questionnaire data and biological samples, and a genomic analysis to perform sequencing of the biological samples and bioinformatics analysis of the sequencing. 

Study phs002814

Comprehensive Genomic Characterization of Translocation Renal Cell Carcinoma

Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the TFE3 gene on chromosome Xp11.2 and a partner gene on either chrX or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics uniquely constrains somatic chrX alterations and underlies cancer sex differences.This version of the dbGaP study provides a comprehensive set of whole genome data and tables with clinical information collected for the 16 patients (15 pateints as tRCC and 1 patient as ccRCC) in the study cohort. The data also contains 12 RNA-seq samples used in the study and analyses. We anticipate that this data will considerably advance our molecular and genetic understanding of oncogenic translocations in TFE3-tRCC involving inactive chromosome X and its role in cancer sex bias.

Study phs003008

Prostate Cancer Upgrading Reference Set

This study aimed to investigate clinical, demographic, and molecular features of men diagnosed with low-risk prostate cancer [ISUP Grade Group 1 (GG1)] at biopsy who underwent radical prostatectomy, and for whom an increased tumor grade (ISUP Grade Group 2 or above) was subsequently detected in the resected prostate. This phenomenon is termed upgrading. In collaboration with the Early Detection Research Network (EDRN), a blinded reference set was established to facilitate upgrading biomarker detection and validation. A prospective, multi-institutional, cohort of men with the GG1 prostate cancer and intention to undergo prostatectomy was recruited. Biospecimens (blood, urine) were collected and this biorepository comprises the official EDRN Upgrading Reference Set (URS). Recording of case-control status (case = upgrading at prostatectomy, control = no upgrading at prostatectomy) was coordinated by the Data Management and Coordinating Center (DMCC) of the EDRN, who ensured blinding of all participating researchers. A subset of the reference set (n = 192) was chosen to undergo whole genome sequencing (WGS) for the investigation of a germline genomic biomarker of upgrading. Variant calls from all sequenced URS whole genomes are available through dbGaP, with the exception of one sample for which sequencing was not successful. Among investigated clinical features, prostate-specific antigen (PSA) density and percent of cancer in pre-prostatectomy positive biopsy cores were significantly associated with upgrading. Two polygenic risk score-based biomarkers were computed in the genetic sub-cohort and tested against case-control status. Neither was predictive of upgrading.

Study phs003670

Field studies of Cryptosporidiosis and Enteropathogens in Bangladesh

Cryptosporidiosis causes severe diarrhea in infants in the developing world. There is no vaccine to prevent it, and little in the way of treatment. This study on Bangladeshi urban slum children aims to support the design of a vaccine, both by determining how the immune system protects from infection and by identifying the genotypes of the parasite that should be included in a vaccine, as well as aid in development of therapies by identifying human genes that control infection. The primary objective of the study was to determine the incidence and contribution to disease of the different species and genotypes of cryptosporidia. Secondary objectives were designed to determine acquired immune response to cryptosporidiosis and identify human genes that influence susceptibility to cryptosporidiosis. This is an observational study. Children were recruited from Mirpur Dhaka slum (Cohort 1) and rural Mirzapur (Cohort 2) and followed for cryptosporidium infection longitudinally from birth through age 4 years in Cohort 1 and birth through age 2 years in Cohort 2. Biweekly household visits for diarrheal surveillance were made in addition to anthropometric measurements of mother and child, blood samples collected two times each year from the child, a work-up of diarrheal stools and non-diarrheal surveillance stools for cryptosporidium and other enteropathogens, and blood and breast milk samples from the mother. A detailed description of the study design and procedures can be obtained from publication: Kevin L Steiner, et al., 2018, PMID: 29897482.

Study phs001665

Identification of RNA biomarkers in Parkinson's disease patients

Parkinson?s disease (PD) is an age-related, chronic and progressive neurodegenerative disorder characterized by a loss of dopaminergic neurons and subsequent motor symptoms. These overt motor symptoms are often preceded by prodromal non-motor symptoms. Though a number of genetic and environmental factors have been identified to play a role in PD, more exact methods for both diagnosing and assessing prognosis are yet to be discovered. By analyzing the transcriptome of early-stage PD patients, this study aims to identify genes (including important non-coding RNAs) and pathways altered at disease onset that may be used as novel biomarkers for PD diagnosis as well as potential new drug targets. The study consists of three main sources of data: first year blood transcriptomes, second year blood transcriptome and matched neural stem cell (NSC)/neuron transcriptomes. All transcriptome libraries were synthesized and sequenced using no-amplification non-tagging cap analysis of gene expression (nAnT-iCAGE) on the Illumina HiSeq 2500 platform. Resulting data was mapped to the human genome annotation (hg38), processed CAGE tags were clustered ready for differential expression analyses. First year blood sequencing consisted of 22 PD patients and 10 healthy controls across four lanes. In the second year, a further four lanes were sequenced containing 17 PD patients (12 patients from the first year and 5 new patients) along with 10 healthy controls and 5 first year blood samples matching the new second year patients.

Study JGAS000119

Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma

In IDH-mutant astrocytomas, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain elusive. Here, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2R172K and TP53R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recurrent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2R172K mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 with PDGFRA gain was found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astrocytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.

Study JGAS000646

Gut metagenome associations with extensive digital health data in a volunteer-based EstMB cohort second timepoint data

As part of the Estonian Biobank, we established the Estonian Microbiome Cohort which includes stool, oral and plasma samples from 2,509 participants and is supplemented with multi-omic measurements, questionnaires, and regular linkages to national electronic health records. Out of the 2,509 Estonian Microbiome Project participants, a sub-cohort of over 300 individuals provided an additional stool sample after a median follow-up period of 4.4 years. All participants of the EstMB cohort gave informed consent for the data and samples to be used for scientific purposes. In the second time point, the participants were instructed to send the samples by post immediately after taking the sample and time their sample collection to avoid shipping on the weekends. In the study, by utilising retrospective medication usage data from the electronic health records and the Estonian microbiome cohort shotgun metagenomics data set (n = 2,509), we systematically evaluate the long-term effects of antibiotics and human-targeted medications on the gut microbiome. We show that past usage of medications is associated with the gut microbiome. For example, the effects of antibiotics, psycholeptics, antidepressants, proton pump inhibitors, and beta-blockers are detectable several years after use. Furthermore, by analysing a subcohort (n >300 individuals) from the second time point, we show that similar changes in the gut microbiome occur after treatment initiation or discontinuation, possibly indicating causal effects.

Study EGAS50000001181

Nanopore sequencing enables allelic phasing of FLG loss-of-function variants, intragenic copy number variation and methylation status in atopic dermatitis and ichthyosis vulgaris

Loss-of-function (LoF) variants in the FLG gene are associated with ichthyosis vulgaris (IV) and atopic dermatitis (AD). IV and AD patients with two FLG LoF variants are reported to have a more severe disease course. However, subsets of compound heterozygous patients display phenotypic heterogeneity despite a prediction of a severe phenotype from their genotype. The underlying genetic mechanism of this phenotypic variability is unknown. One possibility is that two LoF FLG variants could be located in cis (on the same allele), thus altering the predicted gene dosage. To investigate the allelic contribution of compound heterozygous FLG LoF mutations to IV phenotypic variability, we employ long reads from Oxford Nanopore Technologies, utilising two methodologies to phase the entire coding region of FLG into parental alleles: an amplicon-sequencing approach and an adaptive-sampling strategy. We investigated the allelic phasing of FLG LoF variants and intragenic-repeat copy-number variations (CNV) of 21 subjects with known compound heterozygous genotypes and mixed IV severity. Our results suggest that IV severity is not linked to the presence of cis variants in our IV patient cohort. Nanopore reads enabled detection and accurate phasing of CNVs and LoF variants into parental alleles, providing a framework for future in-depth genetic analysis. These results highlight the usefulness of utilising long reads for interrogating the FLG gene and other highly repetitive genes for genetic stratification related to clinical phenotypes.

Study EGAS50000000166

Noninvasive prenatal molecular karyotyping from maternal plasma

Fetal DNA is present in the plasma of pregnant women. Massively parallel sequencing of maternal plasma DNA has been used to detect fetal trisomies 21, 18, 13 and selected sex chromosomal aneuploidies noninvasively. Case reports describing the detection of fetal microdeletions from maternal plasma using massively parallel sequencing have been reported. However, these previous reports were either polymorphism-dependent or used statistical analyses which were confined to one or a small number of selected parts of the genome. In this report, we reported a procedure for performing noninvasive prenatal karyotyping at 3 Mb resolution across the whole genome through the massively parallel sequencing of maternal plasma DNA. This method has been used to analyze the plasma obtained from 6 cases. In 5 cases, fetal microduplications or microdeletions have been detected successfully from maternal plasma. The two cases with fetal microduplications represented the first noninvasive prenatal detection of such changes from maternal plasma. In the remaining case, the plasma DNA sequencing result was consistent with the pregnant mother being a carrier of a microduplication. Simulation analyses were performed for determining the number of plasma DNA molecules that would need to be sequenced and aligned for enhancing the diagnostic resolution of noninvasive prenatal karyotyping to 2 Mb and 1 Mb. In conclusion, noninvasive prenatal molecular karyotyping from maternal plasma by massively parallel sequencing is feasible and would enhance the diagnostic spectrum of noninvasive prenatal testing.

Study EGAS00001000439

Single cell transcriptomics in expanded Tregs of APS-1 patients

Aim of study: Exploring single cell transcriptomics in expanded Tregs of with autoimmune polyendocrine syndrome type 1 (APS-1) patients (global gene expression, immune panel, TCR). N= 9 APS-1 patients and 9 healthy controls Protocol 1. Regulatory T cells (Tregs) were isolated from EDTA-blood, activated with anti-CD3/CD28 and IL2, expanded in cell culture for 14 days and stored at -150℃ in AB serum or FBS + 5% DMSO until use. 2. Cells were thawed, run through a Live/Dead column and carefully counted. 10000 Tregs were used as input for the 10x protocol. 3. cDNA was generated and amplified using Single Cell VDJ 5’ Gel Beads, Chromium Next GEM Chip K Single cell Kit, Next GEM Single Cell 5’ GEM Kit v2 and 5’ Feature Barcode Kit (all from 10x genomics). 4. Gene expression (GEX) libraries were generated by using the Library Construction Kit from 10x genomics. 5. T-cell receptor (TCR) libraries were generated using the Single Cell Human TCR Amplification Kit and the Library Construction Kit from 10x genomics. 6. 10x Genomics Target Hybridization Kit and Human Immunology Panel was used with GEX libraries. Only 8 patient samples and 8 control samples were used for the immune panel. 7. All libraries have a unique sample index (Dual Index TT Set A). 8. All samples were sequenced on Illumina NovaSeq 6000 on a NovaSeq S2 flow cell.

Study EGAS50000000181

Integration of genomics and histology reveals diagnosis and effective therapy of refractory cancer of unknown primary with PDL1 amplification (H021)

Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multi-agent chemotherapy. Molecular profiling within a clinical whole-exome and transcriptome sequencing program revealed a heterozygous, highly amplified KRAS G12S mutation, compound-heterozygous TP53 mutation/deletion, high mutational load, and focal amplification of chromosomes 9p (including PDL1 [CD274] and JAK2) and 10p (including GATA3). Integrated analysis of molecular data and conventional histopathology suggested a diagnosis of triple-negative breast cancer (TNBC) and provided a rationale for immune checkpoint inhibitor therapy with pembrolizumab, which resulted in rapid clinical improvement and a lasting partial remission. Analysis of 157 TNBC samples from The Cancer Genome Atlas revealed focal, high-level PDL1 amplification coinciding with excessive PDL1 mRNA expression in 24% of cases. Collectively, these results illustrate the diagnostic utility of multidimensional tumor profiling in cases with non-descript histology and immune phenotype, demonstrate the predictive power of genomic PDL1 amplification for immune checkpoint inhibition, and suggest a targeted therapeutic strategy in chromosome 9p24.1/PDL1-amplified cancers.H021

Study EGAS00001001846

UK10K COHORT TWINSUK

The UK10K project proposes 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 directly analyse 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 TwinsUK samples will be part of the cohort study and will undergo whole genome sequencing. For further information with regard to this cohort please contact Brent Richards (brent.richards@kcl.ac.uk) or Nicole Soranzo (ns6@sanger.ac.uk).

Study EGAS00001000108

Performance comparison of three DNA extraction kits on human whole-exome data from formalin-fixed paraffin-embedded normal and tumor samples

We generated 42 human whole-exome sequencing data sets from fresh-frozen (FF) and FFPE samples. These samples include normal and tumor tissues from two different organs (liver and colon), that we extracted with three different FFPE extraction kits (QIAamp DNA FFPE Tissue kit and GeneRead DNA FFPE kit from Qiagen, Maxwell\textsuperscript{TM} RSC DNA FFPE Kit from Promega). Variant calling analysis shows a very high rate of concordance between matched FF / FFPE pairs and equivalent performance for the three kits we analyzed. We find a significant variation in the difference of total number of variants called between FF and FFPE samples for the three different FFPE DNA extraction kits. Coverage analysis shows that FFPE samples have less good indicators than FF samples, yet the coverage quality remains above accepted thresholds. We detect limited but significant variations in coverage indicator values between the three FFPE extraction kits. Globally, the GeneRead and QIAamp kits have better variant calling and coverage indicators than the Maxwell kit on the samples used in this study, although this kit performs better on some indicators and has advantages in terms of practical usage. Taken together, our results confirm the potential of FFPE samples analysis for clinical genomic studies, but also indicate that the choice of a FFPE DNA extraction kit should be done with careful testing and analysis beforehand in order to maximize the accuracy of the results.

Study EGAS00001002631

Long-read trio sequencing of unsolved patients with intellectual disability

Long-read sequencing (LRS) has the potential to comprehensively identify all medically-relevant genome variation, including variation commonly missed by short read sequencing (SRS) approaches. To determine this potential, we performed LRS up to 40x coverage using the Pacific Biosciences Sequel instrument for 5 patient-parent trios with intellectual disability, whose aetiology remained unresolved after SRS exomes and genomes. A first systematic assessment of LRS coverage showed that ~35Mb of the genome was only accessible by LRS and not SRS. Structural variant (SV) calling yielded on average 28,292 SV calls per individual, totalling 12.9 MB of sequence. Trio-based analyses showed concordance for up to 95% of these SV calls across the genome, and 80% of the LRS SV calls were not identified by SRS. De novo mutation analysis did not identify any de novo SVs, confirming these are rare events. Because of high sequence coverage, we were also able to call single nucleotide substitutions. On average, we identified 3 million substitutions per genome, with a Mendelian inheritance concordance of up to 97%. Of these, approximately 100,000 were located in the ~35Mb of the genome that was only captured by LRS. Moreover, these variants affected the coding sequence of 64 genes, including 32 known to cause Mendelian disorders. Although no clinical diagnoses were made in these 5 patients, our data show the potential added value of LRS compared to SRS for identifying medically relevant genome variation.

Study EGAS00001004319

The Southern African Human Genome Programme

The Southern African Human Genome Programme (SAHGP) is a national and regional initiative that aims to unlock the unique genetic character of southern African populations. Its vision is to improve quality of life through understanding human genetic diversity. It is timely to advance the SAHGP initiative since global genomic initiatives are increasingly pointing to populations in Africa, more specifically the San and Khoe from southern Africa, as harbouring the most ancient genetic signatures among the living populations of the world. Studies on African populations have already generated a wealth of information upon which the SAHGP can build. This information will be used to promote and support genomic research programmes both nationally and regionally to address critical questions that would benefit the people of our region. The SAHGP aims to make a significant contribution to the understanding of DNA variation among southern Africans and how this impacts on the health of the people of this region. Aims of the SAHGP: To develop capacity for genomic research in southern Africa; To establish sustainable resources for genomic research in the region; and To translate knowledge and information into improvements in human health in the region. The objective is to derive the maximum benefit from the SAHGP, and that the data should be widely shared with the scientific community for the benefit of the people of the sub-continent and beyond.

Study EGAS00001002639

Disease and phenotype relevant genetic variants identified from histone acetylomes in human hearts

Identifying genetic markers for heterogeneous complex diseases such as heart failure has been challenging, and may require prohibitively large cohort sizes in genome-wide association studies (GWAS) in order to demonstrate statistical significance1. On the other hand, chromatin quantitative trait loci (QTL), elucidated by direct epigenetic profiling of specific human tissues, may contribute towards prioritising variants for disease-association. Here, we captured non-coding genetic variants by performing enhancer H3K27ac ChIP-seq in 70 human control and end-stage failing hearts, mapping out a comprehensive catalogue of 47,321 putative human heart enhancers. 3,897 differential acetylation peaks (FDR < 0.05) pointed to recognizable pathways altered in heart failure (HF). To identify cardiac histone acetylation QTLs (haQTLs), we regressed out confounding factors including HF disease status, and employed the G-SCI test2 to call out 1,680 haQTLs (FDR < 0.1). A subset of these showed significant association to gene expression, either in cis (180), or through long range interactions (81), identified by Hi-C and Hi-ChIP performed on a subset of hearts. Furthermore, a concordant relationship was found between the gain or disruption of specific transcription factor (TF) binding motifs, inferred from alternative alleles at the haQTLs, associated with altered H3K27ac peak heights. Finally, colocalisation of our haQTLs with heart-related GWAS datasets allowed us to identify 62 unique loci. Disease-association for these new loci may indeed be mediated through modification of H3K27-acetylation enrichment and their corresponding gene expression differences.

Study EGAS00001003586

Spatio-temporal Profiling of a Rhabdoid Tumor Case Study

Background Immune checkpoint inhibition (ICI) has revolutionized oncology, offering extended survival and long-term remission in previously incurable cancers. While highly effective in tumors with high mutational burden, lowly mutated cancers, including pediatric malignancies, present low response rate and limited predictive biomarkers. Patients and methods We present a framework for the identification and validation of tumor-reactive T cells as a biomarker to quantify ICI efficacy and as candidates for a personalized TCR-T cell therapy. Therefore, we profiled a pediatric malignant rhabdoid tumor patient with complete remission after ICI therapy using deep single-cell T cell receptor (TCR) repertoire sequencing of the tumor microenvironment (TME) and the peripheral blood. Results Tracking T cell dynamics longitudinally from the tumor to cells in circulation over a time course of 12 months revealed a systemic response and durable clonal expansion of tumor-resident and ICI-induced TCR clonotypes. We functionally validated tumor reactivity of TCRs identified from the TME and the blood by co-culturing patient-derived tumor cells with TCR-engineered autologous T cells. Here, we observed unexpectedly high frequencies of tumor-reactive TCR clonotypes in the TME and confirmed T cell dynamics in the blood post-ICI to predict tumor-reactivity. Conclusion These findings strongly support spatio-temporal tracking of T cell activity in response to ICI to inform therapy efficacy and to serve as a source of tumor-reactive TCRs for personalized TCR-T designs.

Study EGAS00001008174

Genomic Sequencing of Solitary Fibrous Tumors

Solitary fibrous tumors (SFTs) are rare mesenchymal tumors that can be benign or malignant. In this study, we sequenced and analyzed the exomes of 17 SFT matched tumor and normal pairs. This study appertains to a large endeavor to characterize cancers as part of the Slim Initiative for Genomic Medicine in the Americas (SIGMA) project.

Study phs000568

NHLBI TOPMed: The Vanderbilt Atrial Fibrillation Registry (VU_AF)

The Vanderbilt Atrial Fibrillation (AF) Registry was founded in 2001. Patients with AF and family members are prospectively enrolled. At enrollment a detailed past medical history is obtained along with an AF symptom severity assessment. Blood samples are obtained for DNA extraction. Patients are followed longitudinally along with serial collection of AF symptom severity assessments.

Study phs001032

Multimodal Genomic Features Predict Outcome of Immune Checkpoint Blockade in Non-small Cell Lung Cancer

This study evaluates integrated genomic models of response to immune checkpoint blockade for lung cancer patients. A computationally adjusted tumor mutation burden was combined with HLA class I genetic variation, mutational smoking signature and activating mutations in receptor tyrosine kinase genes to generate a prognostic classifier that outperforms tumor mutation burden.

Study phs001940

Genome Wide Association Studies in ECOG 2997 Trial

The ECOG 2997 trial was a randomized controlled trial for patients with previously untreated CLL comparing fludarabine monotherapy to the combination of fludarabine and cyclophosphamide. The initial clinical findings of this study were published in the Journal of Clinical Oncology in 2007 (JCO 25:793-8). Additional laboratory studies have also published (JCO 25:799-804).

Study phs000621

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

Spatiotemporal Analysis of the Human Cerebellum

We sought to characterize neural progenitors within spatially demarcated regions of the human cerebellum at a molecular level during neurogenesis. We used laser-capture microdissection to enrich for cells within the ventricular zone and subventricular zone regions of the rhombic lip, external granule cell layer and Purkinje cell layer, then performed RNA-sequencing on the enriched samples.

Study phs001908

RareBliss: Rare Bipolar Loci Identification Through Sequencing Study

Bipolar disorder is a complex psychiatric disease for which few causative genes have been discovered. Targeted sequencing of bipolar cases and unaffected controls was performed to elucidate the contribution of rare variants to bipolar disorder. This study included the standard exome targets as well as genes involved in synaptic function and genes previously implicated in bipolar disorder.

Study phs001358

Vulnerabilities of Midbrain Dopaminergic Neurons to Parkinson's Disease Revealed by Single-Cell Genomics

We developed a novel protocol for the enrichment of midbrain DA neurons from frozen tissue. We subsequently performed single-nuclei RNA-sequencing on enriched samples from postmortem midbrain tissue from human, macaque, tree shrew, rat, and mouse. We identified vulnerable and resistant populations from these data and associated genetic enrichments and differential expression changes.

Study phs002879

Exome Sequencing of Pleuropulmonary Blastoma

Pleuropulmonary blastoma (PPB) is a rare, aggressive pediatric cancer arising from the lung or pleural cavity. In this study, we sequenced and analyzed the exomes of 15 PPB matched tumor and normal pairs. This study is part of a larger effort to characterize pediatric cancers as part of the Slim Initiative for Genomic Medicine (SIGMA) project.

Study phs000543

Genetic Etiology of Hypoplastic Left Heart Syndrome

To understand the genetic etiology of hypoplastic left heart syndrome (HLHS), patients with HLHS were consented and recruited, with blood drawn for DNA extraction and exome sequencing. Using the exome sequencing dataset obtained, rare coding sequence variants were recovered and enrichment analysis was carried out to identify genes and pathways that are likely to contribute to HLHS.

Study phs001256

Rapid Acceleration of Diagnostics - Digital Health Technologies' (RADx-DHT) Collection of General Research Use Datasets

This individual-level collection of datasets contains all the RADx Digital Health Technologies (RADx-DHT) studies in dbGaP for General Research Use (GRU). Access to studies in this collection is on the RAPIDS platform. To request access to this study collection, select phs003666 in the dbGaP when submitting a data access request.

Study phs003666

iNHL WXS Data Commitee

The iNHL WXS Data Commitee is responsible for managing access to datasets submitted to the European Genome-phenome Archive (EGA). Our committee ensures that access requests are evaluated in compliance with ethical guidelines, regulatory requirements, and the conditions specified by data submitters. Researchers requesting access to these datasets must provide a clear and valid scientific purpose, demonstrate affiliation with a recognized institution, and agree to the terms of use outlined in the Data Access Agreement. The iNHL WXS Data Commitee works to uphold data privacy and security while facilitating responsible data sharing to advance scientific discovery. For further information on our policies or the application process, please contact Hauke Busch (hauke.busch@uni-luebeck.de).

Dac EGAC50000000488

Data access policy

Investigators who download restricted data from this dataset should: - Not attempt to identify individual human research participants from whom the data were obtained. - Acknowledge in all oral or written presentations, disclosures, or publications the specific dataset(s) or applicable accession number(s) and the repositories through which the investigator accessed any data. Any user requesting access to this data must apply for authorization, which is granted by the Data Access Committee (DAC). The DAC will review and approve or disapprove all requests from the research community for data access. Decisions to grant access are made based on whether the request conforms to the specifications of the Research Ethics Committee approval and program specific requirements or procedures (if any).

Dac EGAC50000000504

TIGER-LC High-Throughput Sequencing

Intrahepatic cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) are clinically disparate primary liver cancers with etiological and biological heterogeneity. We performed sequencing on multiple data levels of Thai CCA and HCC among the Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC) cohort using targeted OncoVar platform, whole exome, whole transcriptome, and whole genome metagenomic sequencing.

Study phs001199

An epidemiological study examining the relationship among food, health, and genome

We conducted a cohort-based study to investigate the association between the genetic background and diet/lifestyle in 962 healthy Japanese. We analyzed the Ebetsu cohort and some participants living in Tokyo. The SNP array (Japonica Array v2) was used for genotyping. Shotgun metagenomic sequencing of fecal microbiome and metabolome of feces and blood were analyzed.

Study JGAS000678

Ribosomal profiling on Epstein-Barr virus transformed B-lymphoblastoid cell lines

Epstein-Barr virus-transformed B-lymphoblastoid cell lines from six individuals (HG00114, HG00282, NA12005, NA12044, NA12717 and NA12751) of the GEUVADIS Project were selected for ribosomal profiling. For each EBV-LCL, 20 million cells were treated with 2 μg/ml harringtonine and 100 μg/ml cycloheximide. After lysing cells in lysis buffer supplemented with 100 μg/ml cycloheximide, ribosome complexes were purified by density purification. Small RNA molecules were isolated using the NucleoSpin miRNA Kit (Bioke, Leiden, Netherlands), followed by RNA PAGE gel separation. Universal linkers were added after dephosphorylation. After reverse transcription, the cDNA was circularized and, after ribosomal RNA depletion, barcoded and sequenced on Illumina NextSeq 500.

Dac EGAC50000000209

Whole genome sequence: cardiomyopathy, 1 myotonic dystrophy patient

In this study, we analyzed the genomic information by whole genome sequencing using peripheral blood samples from patients with various cardiovascular diseases including severe heart failure to identify genetic variants related to the pathology of cardiovascular diseases. The purpose is to elucidate the underlying mechanism and develop new therapeutic interventions for cardiovascular disease.

Study JGAS000706

Target sequencing of 11 hereditary breast cancer genes in Japanese

We performed a case control association study for variants in coding regions of 11 hereditary breast cancer genes in 7,051 female unselected breast cancer patients, 11,241 female controls, 53 male patients, and 12,490 male controls of Japanese ancestry. The 11 genes were ATM, BRCA1, BRCA2, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, STK11, and TP53.

Study JGAS000140

The prevalence and clinical characteristics of TECTA-associated autosomal dominant hearing loss.

TECTA is well known as the causative gene for autosomal dominant mid-frequency hearing loss observed in various populations. In this study, we performed next-generation sequencing analysis of a large Japanese hearing loss cohort from unrelated autosomal dominant hearing loss families, to estimate the prevalence and phenotype-genotype correlations in patients with TECTA mutations.

Study JGAS000201

Transcriptome analysis of adolescents and young adults with Acute Lymphoblastic Leukemia

The primary purpose of the research is identification of novel chromosome translocations in adolescents and young adults (AYA) with Acute Lymphoblastic Leukemia (ALL). We searched for novel chromosome translocations in 99 philadelphia-chromosome negative ALL cases (including 76 AYA cases) by RNA-seq using next-generation sequencers, and have discovered some novel chromosome translocations.

Study JGAS000047

CAGEKID: 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.

Study EGAS00001000083

Prospective Lynch Syndrome Database materials

The Prospective Lynch Syndrome Database data. These data contain necessary clinical tables to reproduce the previous PLSD papers using the clinical tables for individual level cancer incidence by age, sex and MMR gene affected. The tables contain the demographics, individual cancers at given age, and therapeutic and prophylactic surgeries removing total or partial organs.

Study EGAS50000001715

T-bet+ CXCR3+ B cells drive hyperreactive B-T cell interactions in multiple sclerosis

scRNAseq, VDJseq and methylome of non-proliferating and autoproliferating B cells from HDs and MS patients, as well as snRNAseq of highly inflamed meningeal MS brain tissue datasets that have been generated and analyzed for the study "T-bet+ CXCR3+ B cells drive hyperreactive B-T cell interactions in multiple sclerosis".

Study EGAS50000000845

Multiregion exome sequencing of ovarian immature teratomas

Tumor tissue from each of the indicated ovarian and disseminated GCT components was selectively punched from formalin-fixed, paraffin-embedded blocks. Genomic DNA was extracted from these tumor and matched normal tissue samples, with a total of 500 ng of genomic DNA used as input for capture employing the xGen Exome Research Panel.

Study EGAS50000000291

PD1-targeted delivery of an IL-2 variant induces a multifaceted anti-tumoral T cell response in human lung cancer

To explore PD1-IL2v-specific effects on CD8 and CD4 T cells at a transcriptomic level, we performed single-cell RNA sequencing of patient-derived tumor fragments (PDTFs) which were treated with either Isotype (DP47), Isotype-IL2v (DP47-IL2v), anti-PD1 (PembroPGLALA) or PD1-IL2v (PembroPGLALA-IL2v) for 48 hours.

Study EGAS50000000396

Evaluation of the Efficacy and Safety of a Clinical Grade Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Patch: A Pre-Clinical Study

Cardiomyocyte-derived induced pluripotent stem cells (iPSCs) may represent a promising therapeutic strategy for severely damaged myocardium. This study aimed to assess the efficacy and safety of clinical grade human iPSC-derived cardiomyocyte (hiPSC-CM) patches and conduct a pre-clinical proof-of-concept analysis.

Study EGAS50000000188

Copy number analysis of Diamond-Blackfan Anemia (DBA) using SNP array

Diamondâ€“Blackfan anemia (DBA), is a rare congenital anemia that usually presents in infancy. About fifty percent of DBA patients possess mutations in ribosomal protains (RPs). In this study, we performed genomic copy number analysis using SNP arrays for 27 Japanese DBA patients to detect genomic copy number lesions of the RP genes' loci.

Study EGAS00000000105

Enhanced resolution profiling in twins reveals differential methylation signatures of Type 2 Diabetes with links to its complications

We profiled DNA methylation in blood samples from participants of European ancestry from 7 twin cohorts using a methylation sequencing platform targeting regulatory genomic regions encompassing 2,048,698 CpG sites. The results help to improve our understanding of T2D disease pathogenesis and progression and may provide biomarkers for its complications.

Study EGAS50000000197

Heterogeneity and evolution of DNA mutation rates in microsatellite-stable colorectal cancer

A mutation accumulation experiment in colorectal cancer (CRC) derived tumoroids, aimed at measuring the spontaneous rates of accumulation of new single-nucleotide sequence variations in seven microsatellite stable CRCs and one microsatellite unstable CRC. Mutations accumulated over six+six months were identified via whole genome sequencing of clonal tumoroids. 150x WGS for 7 samples.

Study EGAS50000000425

Diagnostic yield and clinical utility of whole-exome sequencing in pediatric patients with rare and undiagnosed diseases in the Czech Republic

In our single-center study, we have launched a pilot program for pediatric patients with undiagnosed diseases in the second-largest university hospital in the Czech Republic. WES was implemented as a first-line test after inclusion in the study as part of the diagnostic workflow.

Study EGAS50000000442

Sex Differences in MAGEL2 Gene Promoter Methylation in High Functioning Autism - Trends from a Pilot Study Using Nanopore Cas9 Targeted Long Read Sequencing

Using DNA extracted from peripheral blood, Cas9-targeted nanopore DNA sequencing was used to analyze MAGEL2 gene, including its entire regulatory construct (chr15:23639316-23651466), for sequence variation and 5-methyl-cytosine (5mC) modification in a cohort of adults with HFA compared to sex- and age-matched NC.

Study EGAS50000000508

RNA-seq from B-ALL patients treated on the ALLG ALL09 study

Dataset contains RNA-sequencing data (fastq files) from 46 patients treated on the Australasian Leukaemia and Lymphoma Group (ALLG) ALL09 study (ACTRN12618001734257). All patients were diagnosed with CD19 positive B-cell acute lymphoblastic leukaemia and were negative for Philadelphia chromosome positive disease. Patient samples (bone marrow or peripheral blood) were taken at diagnosis. mRNA was extracted from lymphoblasts and underwent paired-end sequencing using either the illumina NextSeq (75 bp PE) or MGI DNABSEQ-G400 (100bp PE) platforms. Transcriptomic data was used for identification of genomic drivers of acute lymphoblastic leukaemia (ALL).

Dataset EGAD50000001603

scRNA dataset for 15 samples

This dataset includes single cell (sc)RNA-seq of N=3 patient-derived xenograft (PDX) samples profiled at baseline (no drug treatment) and N=12 samples from one PDX profiled during the course of treatment (N=1 sample each for 4 treatment arms x 3 timepoints). The dataset includes bam files that have been purged of reads mapping to cells where a majority of the reads from that cell mapped to the mouse genome. All scRNA-seq data were generated using the Chromium Next GEM Single Cell 5' Reagent Kits v2 (Dual Index) from 10X Genomics.

Dataset EGAD50000001424

Samples obtained within X-pand project

This dataset contains five bone marrow samples and three mobilised peripheral blood ones from different healthy individuals. The three bone marrow samples have been sequence with the 10x multiome kit using Illumina sequencers. The three mobilised peripheral blood ones have been split in two aliquots, one for 10x multiome and the other for 10x CITE-seq. Both libraries types have been sequenced with an Illumina sequencer. Raw data has been processed with cell-ranger and map to the human genome (GRCh38) to obtain the bam files.

Dataset EGAD50000001108

Tumor Normal Pair for SV mosaic

Simulated (based on real world data) tumor normal pair designed for benchmarking and optimisation of structural variation callers. The calls are derived from 12 patients in the hartwig database requested by the EUCANCan project. Paired-end sequencing data was imputed into the normal reference data to simulate real world variation like purity as well as technical impact of sequencing technologies. The dataset contains a tumor sequenced to ±90x depth and a normal control sequenced to ±30 x depth of these imputed events. The break junctions of all detected SVs in the original cases are imputed in this data from diagnostic WGS sequencing data.

Dataset EGAD50000000668

Bulk RNA-seq of monocytes and in vitro cultured monocyte-derived macrophages of ANCA-associated vasculitis patients with active and stable disease and healthy controls

To study monocyte and macrophage activation in ANCA-associtated vasculitis (AAV), we performed bulk RNA sequencing of bead-selected monocytes and in vitro cultured monocyte-derived macrophages from AAV patients and healthy controls. Overview patients included for sequencing monocytes: - AAV active disease, n=4, MPO-AAV=4 - AAV remission, n=10, PR3-AAV=5, MPO-AAV=5 - Healthy controls, n=6 Overview patients included for sequencing monocyte-derived macrophages: - AAV active, n=1, PR3-AAV=1 - AAV remission, n=3, PR3-AAV=3 - Healthy controls, n=3

Dataset EGAD50000000450

SC_DDD-G-5

Post-QC (pre-imputation) genotype data for N=2,166, a subset of trios described in EGAD00010001602. These data form N=722 complete trios in which the proband has a neurodevelopmental phenotype (Niemi et al. Nature 2018). Includes HPO phenotype terms for patients. Samples were genotyped on the Illumina HumanOmniExpress BeadChip

Dataset EGAD00010001606

Biomarker analysis and treatment dynamics following preoperative ipilimumab plus nivolumab in locally advanced urothelial cancer from the phase 1B NABUCCO study

In the current analysis of the full NABUCCO trial population (cohorts 1 and 2), we aimed to explore both potential biomarkers for response to combination ICB, as well as treatment dynamics to gain a better understanding of the effects of ICB on the urothelial cancer tumor microenvironment (TME).

Study EGAS50000001781

Somatic copy number alterations profiling in non-small cell lung cancer and their correlation with clinical efficacy in first-line treatment

Genomic data from FFPE tumor samples of patients with non-small cell lung cancer (NSCLC), profiled by shallow whole-genome sequencing (sWGS). The study aimed to characterize somatic copy number alterations (SCNAs) and SCNA burden to assess their clinical relevance for patient stratification across different first-line treatments.

Study EGAS50000001619

Ribosome_Profiling_of_Macrophages_during_Salmonella_Infection

The aim of this study is to assess translational changes in macrophages over a time course of Salmonella infection. 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 EGAS00001001285

Panel-based next-generation sequencing study of human liver samples.

Panel-based next-generation sequencing study of 150 human surgical liver samples from Caucasian donors with detailed medical documentation. The overall purpose of the study was to identify expression quantitative trait loci (eQTL) in human liver for genes involved in absorption, distribution, metabolism and excretion of drugs, other xenobiotics, and endogenous substances.

Study EGAS00001003426

Investigation of relapse prediction in infants with MLL-rearranged Acute Lymphoblastic Leukemia

In infants with ALL, accurate relapse prediction would enable treatment strategies that take relapse risk into account, with potential benefits for both low- and high-risk patients. Through analysis of bone marrow biopsies taken at initial diagnosis, we show that single-cell RNA sequencing can predict future relapse occurrence.

Study EGAS00001003986

Phased whole genome sequencing of 10 melanoma samples

We have sequenced 10 melanoma samples using 10X linked reads technology to obtain phased whole genome sequence data. Using this data, we created diploid personalized genomes for each sample and aligned functional genomics data obtained from the same samples in order to find allele specific events (such as allele-specific binding and allele-specific chromatin accessibility).

Study EGAS00001004136

TTV018_RORC_IBD_associated_genotype_effects_on_RORgT_expression_and_function_in_ex_vivo_T_cells

RNA sequencing of peripheral immune cells from patients +/- an IBD risk variant. Peripheral immune cells +/- in vitro test compound treatment.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 EGAS00001001590

Unraveling_the_genetic_basis_of_a_collagen_migration_defect_in_patients_with_a_combined__platelet_dysfunction_and_reduced_bone_density

In this project we study cases from unrelated pedigrees that present at a young age with a phenotype which inludes hypotonia and hypodensity of bones, a chronic elevation of some liver and muscle enzymes as well as abnormal platelet number and volume. We aim to use exome sequencing to discover the causative variants reponsible for these defects.

Study EGAS00001000093

Exome sequencing of 142 gastric cancer and matched normal from Japanese cohorts (UT)

As a contribution to the International Cancer Genome Consortium, exome sequencing of 142 Japanese gastric cancer with various histological subtypes have been conducted. This study aims to identify unique and common driver genes and molecular subtypes in Japanese gastric cancer. Please refer ICGC website for detail: http://icgc.org/icgc/cgp/69/420/1012357

Study EGAS00001002891

Chromatin_accessability_in_cytokine_induced_immune_cell_states

We isolated T cells and monocotyes from healthy platelet donors and cultured them in resting and stimulated conditions with addition of a range of cytokines. We performed K27Ac ChM sequencing to assess the chromatin activity in different cytokines treated cells. These cellular profiles were used to map risk variants to the cytokine-induced cell states relevant for autoimmune diseases.

Study EGAS00001002749

SPATC1L variants associated with age-related and hereditary hearing loss

Next-Generation Sequencing techniques (i.e, targeted re-sequencing and whole exome sequencing) have been employed for the study of two Italian patients affected by age-related hearing loss and of an Italian family affected by hereditary hearing loss. Data analysis led to the identification of three variants in SPATC1L, associated with the clinical phenotype.

Study EGAS00001003047

Chromatin_accessability_in_cytokine_induced_immune_cell_states

We isolated T cells and monocotyes from healthy platelet donors and cultured them in resting and stimulated conditions with addition of a range of cytokines. We performed ATAC sequencing to assess the chromatin accessability in different cytokines treated cells. These cellular profiles were used to map risk variants to the cytokine-induced cell states relevant for autoimmune diseases.

Study EGAS00001003501

2014 chunnam AML analysis

2014 AML analysis is conducted with samples collected from Chunnam universty. 67 paired samples are belong to this project. The study was designed to examine the molecular abnormalities from leukemic patients at initial diagnosis in comparison with corresponding germ line control (saliva samples). The results of WXS were analyzed by Mutect for ranking cancer variants and creating mutational matrix.

Study EGAS00001001082

Exome sequencing of 102 gastric cancer and matched normal from Japanese cohorts (YCU)

As a contribution to the International Cancer Genome Consortium, exome sequencing of 102 Japanese gastric cancer with various histological subtypes have been conducted. This study aims to identify unique and common driver genes and molecular subtypes in Japanese gastric cancer. Please refer ICGC website for detail: http://icgc.org/icgc/cgp/69/420/1012357

Study EGAS00001002892

Genomic landscape of inflammatory breast cancer by whole-genome sequencing

Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer, characterized by a highly invasive and metastatic phenotype, but little is known about its genetic drivers. Here we report whole-genome sequencing (WGS) of 20 newly diagnosed IBC biopsies to characterize for the first time the entire genomic landscape of this disease.

Study EGAS00001004117

Indonesian RNA-seq data

Transcription data were collected to study patterns of functional variation across the broad geography of Indonesia. The region has extremely diverse populations, with very different demographic histories and multiple genetic ancestries. This dataset reports high-throughput RNA-sequencing data for individuals from three islands spanning this geographical region: Mentawai, Sumba and West Papua.

Study EGAS00001003671

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scoop-G-1

GWAS results from Danjou et al, Nature Genetics 2015

ADME_gene_expression

EGAD00010000498

Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments

ITER-FIISC Data Access Committee (WES-CIRdb)

ChIPseq data

Reference epigenome OB56_N_PreA_mRNA-Seq data generated from KEP study

Reference epigenome IPS05_X_NPC_WGBS data generated from KEP study

Reference epigenome IPS06_X_ENeuron_WGBS data generated from KEP study

Modern Aboriginal Australians WGS

MPNST exome and genome

SSBP1 sample

Cancer Alliance RNA-Seq total RNA

Brain mets discovery cohort copy number calls

Germline snv g.vcf for EGAS00001004572

R code