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• Genome-Wide Association Study in Systemic Sclerosis

  The Scleroderma Family Registry and DNA Repository (Registry) was initially developed as a registry and bio-specimen repository of patients with systemic sclerosis (scleroderma), family members and unaffected healthy controls. A case-control design was later adopted due to the lack of availability of many parents in this adult-onset disease, which precluded a linkage approach. In addition to collecting demographic data, the registry included the collection of disease-pertinent, cross-sectional, clinical information from medical records of affected participants. Registry participants were >/= 18 years of age at enrollment. On the basis of medical record review, all cases were verified by the principal investigator to meet the eligibility criteria. 800+ blood samples from verified affected cases of European ancestry were selected for a Genome Wide Association Study (GWAS). These genetic data, as well as phenotypic data, are available in dbGaP. DNA, serum and plasma from Registry participants, which are currently being stored in the University of Texas Health Science Center - Houston, Scleroderma Registry Genetic Repository, are available for research purposes. However, not all of the 800+ registry participants who submitted a blood sample currently have DNA available due to depletion of some samples. In addition to including SNP data from the genome-wide (first study release) and immunochip (second study release) scan on the 800+ samples, the dbGaP database provides a set of data tables with phenotypic information collected from the participants in the registry.

  Study phs000357

• Defining the metastasome in colorectal cancer: Implications for hypotheses on metastasis evolution and personalized therapy (HIPO-032)

  Personalized cancer therapy aims at individual genetic changes characterizing primary cancers. Still, however, metastasis is the major clinically unmet problem, also due to an incomplete understanding of its molecular evolution.This study is the first to define the metastasis-specific whole genome landscape of human colorectal primary vs. matched metastatic lesions.Protein coding, ncRNA genes and 3’UTRs harbored about a third each of single nucleotide variations (SNVs)/indels, 19% of them being metastasis-specific. We found novel mutational hills among ncRNAs and 3’UTRs, copy number changes able to explain changes in microRNA expression in metastases, and novel metastasis-specific mutations in the 3’UTRs on important cancer signalling genes. Some metastatic lesions showed targetable mutations not detected in the primaries. Analysis of mutual exclusivity patterns supported a model that has progressive alterations in important colorectal cancer genes and revealed new partners. Metastatic lesions were enriched in SNVs, specific structural variations, and alterations in genes affecting cell adhesion and extracellular matrix interaction.Furthermore, a hepatic stellate activation cascade was enriched in metastases, suggesting genetic programs for site-specific colonization. Allele frequency distribution and mutational signature analysis suggests a common ancestor clone to both the primary tumor and the metastasis, with additional mutagenesis ongoing in both sites independently. Taken together, our results significantly add to hypothesis generation on metastasis evolution, and suggest novel metastasis-specific genomic changes which would be missed by current personalized therapy concepts. (HIPO-032)

  Study EGAS00001002717

• Identification of drug resistance genes in melanoma

  Our aim is to analyze the genome of human melanoma cell lines and short term culture from human melanoma samples in order to identify genes that confer drug resistance to clinically relevant targeted therapies. We will perform whole-exome sequencing, copy number variation analysis and methylome analysis in a collection of human melanoma cell lines and short term culture that will be then screened for drug sensitivity/resistance through a library of clinically relevant drugs and drug combinations. By the combined analysis of the genomic lesion and the drug sensitivity/resistance profile of different cell lines, we will look for genes whose mutation is associated to the sensitivity or resistance to a specific drug in different samples.

  Dataset EGAD00001001124

• National Heart, Lung, and Blood Institute (NHLBI) Data Coordinating Center, Microbiome of the Lung and Respiratory Track, Lung HIV Microbiome Project (LHMP)

  Humans interact with countless microorganisms in multiple environments. The Lung HIV Microbiome Project (LHMP) characterized the microbiome of the lung and respiratory tract. This effort provided initial data to develop further hypotheses addressing differences between HIV-infected and HIV-uninfected individuals. The project involved multiple studies, either single center or multiple-center studies. The research design of each study varies with the objective of that study. The Lung HIV Microbiome Project (LHMP) worked collaboratively to ensure the clinical and scientific integrity and success of this project. The LHMP characterized the microbiome of the lung alone or in combination with the oropharyngeal cavities in HIV-infected individuals and HIV-uninfected controls using molecular techniques to identify bacteria. Knowledge of the lung microbiome and that of other components of the respiratory tract in healthy and diseased states may lead to the identification of predictors of disease progression and therapeutic targets for translation into better preventive and treatment strategies. Study datasets and biospecimens are available for request from https://biolincc.nhlbi.nih.gov/studies/lhmp/.

  Study phs000769

• Stressors and Health Study

  ObjectivesThe objectives of the Stressors and Health Study were to: (1) examine the prevalence of stressors and health outcomes and (2) assess differences in the associations between multi-level stressors and health outcomes, and (3) explore the protective and adaptive factors in the associations between multi-level stressors and health outcomes. Background Stressors have been posited to explain disparities in health. However, no surveys to our knowledge have simultaneously collected multiple stressors at various levels and the coping strategies used to deal with these stressors. Measuring these factors can provide a better understanding of the stressors experienced by specific groups and the impact that these experiences have on their health and health practices. In addition, exploring the various resilience and coping strategies employed to deal with stressors can help design appropriate interventions to reduce health disparities. Participants Participants included 1000 White, 1000 Black or African American, 1000 Latino or Hispanic, 1000 Asian, 500 American Indian or Alaska Native, 500 Native Hawaiian or Pacific Islander, and 500 mixed or multi-race adults (≥18 years) across the United States. Design The Stressors and Health Study is a cross-sectional online survey of adults across the US. A sampling frame (target population) of US residents based on the American Community Survey (ACS) was constructed using a rigorous two-step sampling matching approach to establish national representation.

  Study phs004019

• Effects of 2DG, Galactose, or Oligomycin on the epigenome remodeling induce by T cells activation.

  T cell activation is known to require a metabolic shift towards glycolysis, triggered by TCR-engagement . To substantiate the role of glycolysis in transcriptional reprogramming during antigen-driven T cell activation, we utilized a well-established ex-vivo model to recapitulate the process of antigen stimulation without the requirement for additional antigen-presenting cells . We initially explored and validated the conditions for both metabolic and epigenetic reprogramming. Antigen-mediated CD4+ T cells activation initiates context-specific gene-expression programs that drive effector functions and cell fates through changes in the epigenetic landscape . To evaluate global changes in histone modifications, we isolated CD4+ T cells from peripheral blood (PB) of healthy control (HC) human donors and either maintained them in resting conditions or stimulated with anti-CD3/CD28 for 24h. Rapid changes in the CD4+ epigenome and transcriptome were observed within 24h as measured by RNA-sequencing (RNA-seq) and H3K27ac chromatin immunoprecipitation followed by DNA-sequencing (ChIP-seq).To explore the requirement for metabolic reprogramming in regulating transcriptional responses after initial TCR engagement, CD4+ T cells from PB of healthy donors were isolated and activated in either the presence or absence of oligomycin (inhibitor of ATP synthase blocking the production of ATP by OXPHOS), 2-deoxyglucose (2DG; competitively inhibiting production of glucose-6-phosphate from glucose), or replacement of glucose with galactose. Galactose is metabolized through glycolysis, utilizing the Leloir pathway which is energy neutral, forcing cells to use all the pyruvate production to sustain the TCA cycle for OXPHOS and ATP synthesis at the expense of lactate production. Employing ChIP-seq and RNA-seq, inhibition of OXPHOS-mediated ATP production by oligomycin had only a limited effect on H3K27-acetylation or activation-induced transcription during the first 24h of activation. In contrast, inhibition of glycolysis by 2DG treatment compromised both H3K27-acetylation and transcriptional changes. However, under conditions of galactose-metabolism where lactate production is abrogated, activated CD4+ T cells were still able to globally remodel H3K27 acetylation and reprogram the transcriptome.

  Study EGAS00001007115

• Study on the consequences of prenatal famine exposure on DNA methylation.

  The potential of the epigenome to undergo environmentally-induced changes during early development is central to its postulated role in human disease. Here, we report a genome-scale view of DNA methylation differences after early gestational malnutrition that was caused by the Dutch Hunger Winter, a severe famine at the end of World War II. We adopted an annotation guided analysis of reduced-representation bisulfite sequencing data generated in 24 middle-aged individuals who had been exposed to famine in utero and 24 unexposed sibling controls. We observed differential DNA methylation primarily at genomic regions with regulatory potential, including enhancers active during early development. In-depth annotation of 181 prenatally-induced differentially methylated regions (P-DMRs) showed that they were predominantly located in gene bodies and co-occurred with histone marks denoting an active state. In line with the early gestational timing of the exposure, the P-DMRs mapped to genes that were enriched for differential expression patterns during blastocyst development and early organogenesis. Validation and further explorative analyses of 6 P-DMRs mapping to SMAD7, CDH23, INSR, RFTN1, CPT1A and KLF13 highlighted the critical role of gestational timing, indicated that differential methylation extended along pathways involved in growth, development and metabolism, and suggested associations with birth weight and serum LDL cholesterol in adulthood and confirmed an enhancer function for the INSR and CPT1A P-DMRs. Our results point toward a link between prenatal malnutrition and epigenetic modulation of growth and lipid metabolism that may underlie the adverse metabolic phenotype of exposed individuals in later life.

  Study EGAS00001000668

• The_GENCODE_exome___sequencing_the_complete_human_exome

  We report the design of an extended set of targets for capturing the complete human exome, based on annotation from the GENCODE consortium. The extended set covers an addition 5,594 genes and 10.3 Mb compared to current sets which mainly target the CCDS database. The additional regions include potential disease genes previously inaccessible to exome resequencing studies, such as 43 genes linked to ion channel activity and 70 genes linked to protein kinase activity. In total, the new GENCODE exome set developed covers 47.9Mb and performed well in sequence capture experiments with HapMap and clinical samples. Samples within this study are prepared with either the CCDS or GENCODE exome products.

  Study EGAS00001000016

• Genome Diversity in Africa Project: Benin (2021-02-16)

  Globally, human populations show structured genetic diversity as a result of geographical dispersion, selection and drift. Understanding this genetic variation can provide insights into the evolutionary processes that shape both human adaptation and variation in disease. Populations from SSA have the highest levels of genetic diversity. This characteristic, in addition to historical genetic admixture, can lead to complexities in the design of studies assessing the genetic determinants of disease and human variation. However, such studies of African populations are also likely to provide new opportunities to discover novel disease susceptibility loci and variants and refine gene-disease association signals. A systematic assessment of genetic diversity within SSA would facilitate genomic epidemiological studies in the region. The Genome Diversity in Africa Project (GDAP) aims to produce a comprehensive catalogue of human genetic variation in SSA, including single nucleotide polymorphisms (SNPs), structural variants, and haplotypes. This resource will make a substantial contribution to understanding patterns of genetic diversity within and among populations in SSA, as well as providing a global resource to help design, implement and interpret genomic studies in SSA populations and studies comprising globally diverse populations, complementing existing genomic resources. Specifically, we plan to carry out high depth whole genome sequencing of up to 2000 individuals across Africa (25 individuals from each ethnolinguistic group). Our scientific objectives are to: 1) develop a resource that provides a comprehensive catalogue of genetic variation in populations from SSA accessible to the global scientific community; 2) characterise population genetic diversity, structure, gene flow and admixture across SSA; 3) develop a cost-efficient, next-generation genotype array for diverse populations across SSA; and 4) facilitate whole genome-sequencing association studies of complex traits and diseases by developing a reference panel for imputation and resource for enhancing fine-mapping disease susceptibility loci. These scientific objectives will be supported by cross-cutting operational activities, including network and management of the consortium, research ethics, and research capacity building in statistical genetics and bioinformatics 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/ . This dataset contains all the data available for this study on 2021-02-16.

  Dataset EGAD00001006970

• Determination of Cross-Reactive Immunological Material (CRIM) status and longitudinal follow-up of individuals with Pompe disease

  Infantile-onset Pompe disease is an inherited disorder that is normally diagnosed within the first months of life. It is caused by lack of or defect in an enzyme (a special protein that carries out normal chemical reactions within the body) called acid alpha-glucosidase (GAA). GAA normally breaks down glycogen (stored sugar) in lysosomes (the part of the cell that digests food and other chemicals). Pompe disease is one of many lysosomal storage diseases (LSDs). LSDs are diseases caused by the malfunction of the lysosome or one of their digestive enzymes. Patients with Pompe disease cannot break down lysosomal glycogen. This causes glycogen to build up and damage cells throughout the body, especially in the heart and muscles. Current treatment for Pompe disease involves enzyme replacement therapy (ERT). In this treatment, the drug alglucosidase alfa (Myozyme) is put into your blood. The drug provides a form of the GAA enzyme to replace the enzyme that is missing or not working properly in the patient's blood. This treatment has allowed babies to live longer and achieve developmental milestones. In this study, researchers will learn about the patient's ability to tolerate ERT. Cross-Reactive Immunological Material (CRIM) is a measurement of natural GAA production. A patient's CRIM status (either positive or negative) is an important factor that affects how he or she responds to ERT with Myozyme. Children who produce some natural GAA are classified as CRIM+, while children who do not produce any natural GAA are classified as CRIM-. Children who are CRIM+ generally tolerate ERT well. But, children who are CRIM-, and some children classified as CRIM+, have a poor response to ERT. Patients who have a poor response to ERT have complications because their body sees Myozyme as "foreign" and triggers an immune response to try to remove it from the body. Treatments are currently being developed to stop this immune response and prevent complications from ERT. We will enroll patients with Infantile Pompe disease in this longitudinal natural history (observational) study. The specific aims of this study are: To determine and correlate Cross-Reactive Immunological Material (CRIM) status with the GAA gene mutations found on these patients To validate an approach for determining CRIM status from whole blood sample, with the gold standard determination of CRIM status by skin fibroblasts and mutation analysis To explore the clinical treatment response and natural history of CRIM-positive and CRIM-negative Pompe disease patients with and without immune modulation To investigate the role of immune response to treatment

  Study phs001555

• POT1 splice site mutant analysis

  We are interested in the contribution mutations in the Shelterin complex protein POT1 may have to the development of melanoma. We have identified a patient who carries a splice site mutation in POT1 and as part of our analysis of this gene we aim to sequence the transcriptome of this patient to see how this mutation influences splicing. RNA has been obtained from lymphocytes collected from the patient.

  Dataset EGAD00001000786

• Assessment of Neurological Deterioration in Subjects with Late Infantile Neuronal Ceroid Lipofuscinosis

  Late infantile ceroid lipofuscinosis (LINCL) is a rare, rapidly progressing lysosomal storage disease resulting from mutations in the CLN2 gene that lead to deficiency in the lysosomal protease tripeptidyl peptidase I (TPP-I). The symptoms are largely neurological with onset at 2-4 years age with progression to death at age 8-12 yrs. The rareness of the disease and the likelihood of non-uniform progression depending on genotype together limit the data available regarding the natural history of disease progression. Current neurological rating scales are used to give an overall quantitative description of the disease but the categories are generally broad and imprecise. With that background, the primary focus of this study is to use clinical rating scales and magnetic resonance imaging methods to define the natural history of LINCL and to provide objective and sensitive surrogates for neurological status and the impact of experimental treatments in children with LINCL. Together these parameters will be applicable to future clinical studies of novel therapies for LINCL and should be transferrable to other neurological lysosomal storage diseases. Subjects will be assessed at 2 visits separated by ≥1 yr. Brain morphometry, water self-diffusion coefficients and spectroscopic data will be obtained via magnetic resonance. Resulting MRI biomarkers will be compared with neurological assessment of disease severity using the Weill-Cornell LINCL rating scale.

  Study phs001575

• BMP4 and temozolomide synergize in the majority of patient derived glioblastoma cultures

  The poor prognosis of patients with glioblastoma is partly due to resistance to standard treatment, which combines chemoradiation using temozolomide (TMZ). The concept of cancer stem cells provided new insight into tumor resistance and management, and isolated Glioblastoma stem-like cells (GSCs) which contribute to this therapy resistance. Bone morphogenetic protein 4 (BMP4) is a differentiation factor that stimulates astroglial differentiation of such GSCs, thereby reducing their self-renewal. Exposing GSCs to BMP4 could therefore sensitize them to chemotherapy with TMZ, but previous studies with various treatment paradigms have produced contradictory results in this matter. Therefore, we re-defined the optimal treatment paradigm for the combination of TMZ and BMP4 and subsequently re-assessed the inter-tumoral variability in response to co-treatment with TMZ+BMP4 in vitro. First, the simultaneous treatment was found more effective than sequential therapy. Second, after application of our optimized treatment protocol, 70% of a total of 20 patient-derived glioblastoma cultures showed synergy when the treatments were combined. The synergistic effect was a result of increased cellular apoptosis and not of decreased proliferation. Comparative RNA-sequencing suggested that combination treatment results in decreased MAPK signaling. We conclude that addition of BMP4 to standard therapy with TMZ could enlarge the group of patients with good therapeutic response.

  Study EGAS00001007095

• Structure and evolution of double minutes in diagnosis and relapse brain tumors

  Double minute chromosomes are extrachromosomal circular DNA fragments frequently found in brain tumors. To understand their evolution, we characterized the double minutes in paired diagnosis and relapse tumors from a pediatric high-grade glioma and four adult glioblastoma patients. We determined the full structures of the major double minutes using a novel approach combining multiple types of supporting genomic evidence. Among the double minutes identified in the pediatric tumor, only one carrying EGFR was maintained at high abundance in both samples, whereas two others were resent in only trace amounts at diagnosis but abundant at relapse, and the rest were found either in the relapse sample only or in the diagnosis sample only. For the EGFR-carrying double minutes, we found a secondary somatic deletion in all copies at relapse, after erlotinib treatment, but this was rare at diagnosis, suggesting potential resistance to the EGFR inhibitor. This mutation caused an in-frame RNA transcript to skip exon 16, a novel transcript absent in EST database and in about 700 brain tumors that we reviewed. We observed similar patterns involving longitudinal copy number shift of double minutes in another four pairs (diagnosis / relapse) of adult glioblastoma. Overall, in three of five paired tumor samples, we found that although the same oncogenes were amplified at diagnosis and relapse, they were amplified on different double minutes. Our results suggest that double minutes readily evolve, increasing tumor heterogeneity rapidly. Understanding patterns of double minute evolution can shed light on future therapeutic solutions to brain tumors carrying such variants.

  Study EGAS00001003212

• Landscape of Somatic Mutations in B Lymphocytes Across Human Lifespan

  The accumulation of spontaneous mutations in somatic cells has been implicated as a cause of aging since 1950. Yet, attempts to establish a causal relationship between somatic mutations and aging have been constrained by the lack of methods to directly identify mutational events in primary human tissues. Using a highly accurate single-cell whole-genome sequencing method, we analyzed human B lymphocytes from donors varying in age from birth to over 100 years, studying both genome distribution and functional impact of base substitution mutations.

  Study phs001808

• Filtered variants including SLC12A2 in patients with hearing loss

  Hereditary hearing loss is challenging to diagnose because of the heterogeneity of the causative genes. Further, some genes involved in hereditary hearing loss have yet to be identified. Using whole-exome analysis of three families with congenital, severe-to-profound hearing loss, we identified a missense variant of SLC12A2 in five affected members of one family showing a dominant inheritance mode, along with de novo splice-site and missense variants of SLC12A2 in two sporadic cases, as promising candidates associated with hearing loss.

  Study JGAS000379

• 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

• LifeChange Data Access Committee

  The LifeChange study aimed at tracking the biological consequences of the societal changes undergone by the Yakut people of Far Eastern Siberia, after the colonization of the region by Russians in the 17th century. This study builds upon more than 15 years of archaeological research conducted in Yakutia, Sakha Republic, an autonomous region of the Russian Federation located in northeastern Siberia. The fieldwork was conducted under the MAFSO program (“Mission Archéologique Française en Sibérie Orientale”, or “French Archaeological Mission in Eastern Siberia”), a collaboration between French researchers and local Yakut experts, including scholars from North-Eastern Federal University in Yakutsk. The program was supported by several inter-university collaborative research agreements, notably between Université Paul Sabatier, Krasnoyarsk State Medical University, and North-Eastern Federal University in Yakutsk. It also received endorsement from the Institute of Ecology and Evolution at CNRS through the International Associated Laboratory “Co-evolution Human-Environment in Eastern Siberia”. The LifeChange Data Access Committee, composed of French and Russian archaeogeneticists, geneticists and archaeologists, reviews any access request to LifeChange data, consisting of genomes of ancient and modern Yakut, Eveni and Evenki individuals sampled in Eastern Siberia for the LifeChange study. The DAC grants access to any academic researcher aiming to study the population history of autochthonous peoples from Siberia. When reviewing data access requests, the DAC members ensure that the applicant will not re-use the data to trace present-day descendants of studied ancient individuals. They also ensure that secondary use of the modern genomic data is conducted in full respect of the conditions stipulated in living participants’ informed consent. Specifically, the applicant is not authorised to (i) use the data for diagnostic purposes, (ii) store the data outside of secure servers, (iii) reidentify research participants, and (iv) share the data with a third party.

  Dac EGAC50000000713

• Poikiloderma_syndrome_RNAseq

  We will sequence the RNA of lymphoblast samples, transformed with EBV, which have poikiloderma syndrome with mutations in c16orf57. The aim of the experiment is to characterise RNA structural effects in this disease.

  Study EGAS00001000250

• A New Pipeline to Predict and Confirm Tumor Neoantigens Predicts Better Response to Checkpoint Blockade

  Mutations that drive oncogenesis in cancer can generate neoantigens that may be recognized by the immune system. Identification of these neoantigens remains challenging due to the complexity of the major histocompatibility complex (MHC) antigen and T-cell receptor interaction. Here we describe the development of a systematic approach to efficiently identify and validate immunogenic neoantigens. Whole exome sequencing of tissue from a melanoma patient was used to identify nonsynonymous mutations, followed by MHC binding prediction and identification of tumor clonal architecture. The top 18 putative class I neoantigens were selected for immunogenicity testing via a novel in vitro pipeline in HLA-A201 healthy donor blood. Naive CD8 T cells from donors were stimulated with allogeneic dendritic cells pulsed with peptide pools and then with individual peptides. The presence of antigen-specific T cells was determined via functional assays. We identified one putative neoantigen that expanded T cells specific to the mutant form of the peptide and validated this pipeline in a subset of patients with bladder tumors treated with durvalumab (N = 5). Within this cohort, the top predicted neoantigens from all patients were immunogenic in vitro. Finally, we looked at overall survival in the whole durvalumab-treated bladder cohort (N = 37) by stratifying patients by tertile measure of tumor mutation burden (TMB) or neoantigen load. Patients with higher neoantigen and TMB load tended to show better overall survival.

  Study phs002269

• IDENTIFICATION AND TARGETED MANAGEMENT OF A PATIENT WITH A NEURODEGENERATIVE DISORDER CAUSED BY BIALLELIC MUTATIONS IN SLC5A6

  We describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age. Using whole exome sequencing, compound heterozygous variants were identified in SLC5A6, which encodes the sodium-dependent multivitamin transporter (SMVT) protein. SMVT is an important transporter of the B-group vitamins biotin, pantothenate and lipoate. The protein is ubiquitously expressed and has major roles in vitamin uptake in the digestive system, as well as transport of these vitamins across the blood-brain barrier. Pathogenicity of the identified variants was demonstrated by impaired biotin uptake of mutant SMVT. Identification of this vitamin transporter as the genetic basis of this disorder guided targeted therapeutic intervention, resulting clinically in improvement of the patient’s neurocognitive and neuromotor function. This is the second report of biallelic mutations in SLC5A6 leading to a neurodegenerative disorder due to impaired biotin, pantothenate and lipoate uptake. The genetic and phenotypic overlap of these cases confirms mutations in SLC5A6 as the genetic cause of this disease phenotype. Recognition of the genetic disorder caused by SLC5A6 mutations is essential for early diagnosis and to facilitate timely intervention by triple vitamin (biotin, pantothenate and lipoate) replacement therapy.

  Study EGAS00001003861

• Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic

  Despite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n = 176) and those without (n = 82). Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency < 1% in ESP6500) in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks. "Reprinted from doi:10.1016/j.ebiom.2014.12.003, with permission from EBioMedicine."

  Study phs000942

• Whole genome sequencing of glioblastoma reveals enrichment of non-coding constraint mutations in known and novel genes

  Glioblastoma (GBM) has one of the worst five-year survival rates of all cancers. While genomic studies of the disease have been performed, alterations in the non-coding regulatory regions of GBM have largely remained unexplored. We apply whole-genome sequencing (WGS) to identify non-coding mutations, with regulatory potential in GBM, under the hypothesis that regions of evolutionary constraint are likely to be functional, and somatic mutations are likely more damaging than in unconstrained regions.

  Study EGAS00001004379

• A Comparative Analysis of Algorithms for Somatic SNV Detection in Cancer

  Four recently published algorithms for the detection of somatic SNV sites in matched cancer-normal sequencing datasets are VarScan, SomaticSniper, JointSNVMix and Strelka. In this analysis, we apply these four SNV calling algorithms to cancer- normal Illumina exome sequencing of a chronic myeloid leukaemia (CML) patient. The candidate SNV sites returned by each algorithm are filtered to remove likely false positives, then characterised and compared to investigate the strengths and weaknesses of each SNV calling algorithm.

  Study EGAS00001000927

• UK10K NEURO IMGSAC

  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 IMGSAC cohort is an international collection of families containing children ascertained for ASDs (autism spectrum disorders). The affected individuals are have been phenotyped, including using the ADI-R and ADOS instruments. Individuals with a past or current medical disorder of probable etiological significance or TSC have been excluded. Where possible, karyotyping has been performed on one affected individual per family to exclude Fragile X syndrome. Many of the samples have been genotyped, using the Affymetrix 10k and Illumina 1M platforms. All samples to be included in the current study are of UK origin.For further information on this cohort please contact Jeremy Parr (jeremy.parr@newcastle.ac.uk).

  Study EGAS00001000120