4051 results for "*geneti*"

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• H3Africa - Deciphering Developmental Disorders in Africa

  Developmental disorders are typically rare conditions, causing an impairment in physical, learning, language, or behavioural areas. Genetic heterogeneity and highly variable clinical manifestations make diagnosing developmental disorders particularly challenging. Developmental disorders are increasing in prevalence in low- and middle-income countries, partly due to effective prevention and treatment of infectious diseases leading to a decrease in childhood mortality. New sequencing technologies are used effectively in the diagnosis of rare diseases and results can impact clinical practice significantly. Despite this international trend, very little implementation of these new approaches has taken place in low-resource settings, especially in Africa. The Deciphering Developmental Disorders in Africa (DDD-Africa) study aims to take advantage of an unbiased genotype-driven approach to improve healthcare services for patients. The study aims to recruit and perform detailed clinical phenotyping and exome sequencing (ES) on 500 African patients with a developmental disorder in whom a genetic diagnosis has not been confirmed. Where available, parents are also included in sequencing efforts. The project has two active research sites in Johannesburg (South Africa) and Kinshasa (Democratic Republic of Congo) representing diversity in geography, clinical, socio-economic, genetic and environmental factors.

  Study EGAS00001008319

• Taste Receptor Gene Variants: Body Mass Index (BMI) and Longevity

  We evaluated differences in genotype and allele frequencies at the TAS1R2, TAS1R3, TAS2R38, and CD36 single-nucleotide polymorphisms (SNPs) and their associations with BMI and sex in two genetically and environmentally distinct populations: a cohort of near centenarian participants and a control cohort.

  Study EGAS00001008403

• Transcriptional and translational alterations induced by BET protein inhibition and its combination with Omaveloxolone in acute myeloid leukemia

  The inhibition of bromodomain and extra-terminal domain (BET) protein family achieved promising preclinical results as epigenetic therapy in acute myeloid leukemia (AML). However, clinical data showed a limited activity of bromodomain inhibitor (BETi) as single agent. We aimed to investigate the role of hypoxia in the response of AML cells to BET inhibition in order to identify a novel therapeutic combination targeting leukemia stem-progenitor cells (LSPCs) in their niche. BETi maintained an anti-proliferative and pro-apoptotic activity at low oxygen concentration by modulating the leukemic transcriptional, translational and metabolic programs towards reduced ribosome biogenesis, altered polyamine metabolism and activation of a TNF- via NF-B signature at translational level, especially in hypoxic conditions. Accordingly, Omaveloxolone, a clinical-stage NF-B inhibitor and NFR2 activator approved for Friedreich’s ataxia, significantly enhanced the efficacy of BETi against AML cell lines in hypoxia and normoxia by reducing cell viability and enhancing apoptosis. At molecular level, the drug combination converged to the downregulation of MYC, the DNA replication and oxidative phosphorylation signatures while forcing the expression of antioxidant genes. Overall, the combination of BETi and Oma disrupts key metabolic and transcriptional programs essential to AML cell survival and LSPC maintenance in the hypoxic microenvironment.

  Study EGAS00001008404

• Brazilian biorepository to support genome-wide association studies of colorectal, breast, and cervical cancer

  This study established a large-scale Brazilian biorepository to support cancer GWAS, replication studies, and polygenic risk score (PRS) evaluation for colorectal, breast, and cervical cancers. 4,062 participants have been enrolled, including cancer cases and cancer-free controls. Genotyping was performed in 2,844 participants using the Axiom 850K PMDA Array. Genetic ancestry inference confirmed Brazil’s highly admixed genetic background, with predominant European, followed by African, Native American, and Asian contributions. This biorepository provides a scalable resource to enable replication of genetic associations, assess the transferability of polygenic risk scores, and advance precision medicine in underrepresented populations.

  Study EGAS00001008408

• Genomic and fragmentomic landscapes of cell-free DNA in aging and disease

  Genome-wide analyses of cell-free DNA (cfDNA) are beginning to be used for non-invasive disease diagnosis, but these approaches have not been explored for detection of aging-related diseases. We used low coverage whole genome sequencing (1-2x) to assess variation in cfDNA fragmentomes across 1446 individuals of varying ages with different comorbidities and genetic risk profiles. Analysis of cfDNA fragment characteristics revealed changes in overall concentration and size distributions, as well as alterations in genome-wide fragmentation profiles, chromosomal representation, repeat element landscapes, end-positions, and coverage at epigenetic regions in the circulation of aging individuals. cfDNA fragmentome characteristics were uniquely altered in a variety of human morbidities, including vascular, neurologic, and inflammatory diseases, and were independent predictors of patient outcomes in separate prospectively collected discovery (n=570) and validation (n=231) cohorts. cfDNA fragmentome-based analyses detected Alzheimer’s disease in aging individuals with varying germline risk profiles (n=645). These results identify changes in cfDNA fragmentomes in aging populations and highlight the potential of cfDNA liquid biopsies to provide snapshots of an individual’s physiologic state in health and disease.

  Study EGAS00001008470

• Spatial Omics Resolves Adrenergic and Mesenchymal Cell States in Neuroblastoma

  Neuroblastoma is a pediatric cancer arising from the developing sympathoadrenal lineage. Although cell lines derived from neuroblastoma patients have features of either adrenergic (ADRN) or mesenchymal (MES) cells, identifying MES cells in patient tumors is challenging and controversial. Here, to characterize intra- and inter-patient cellular heterogeneity, we analyze 54 neuroblastoma tumors spanning broad clinical, genetic, and histologic features using single-cell/single-nucleus RNA-sequencing (sc/snRNA-seq), bulk RNA-sequencing, spatial transcriptomics, and spatial proteomics. We show that tumor cells occupy distinct cellular neighborhoods separated from nonmalignant immune and stromal cells, yet established cell line-derived gene expression signatures fail to identify MES neuroblastoma cells. We therefore develop ADRN/MES signatures from early passage orthotopic patient-derived xenografts, enabling identification of MES tumor cells, validated by transcriptomic, epigenomic, proteomic, ultrastructural and functional assays. In patients, high MES gene expression correlates with worse event-free and overall survival. Together, this study provides a framework for defining clinically relevant neuroblastoma cell states.

  Study EGAS00001008537

• A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates whole-genome sequencing outperforms whole-exome sequencing.

  Whole-exome (WES) or whole-genome (WGS) sequencing are recommended as first- or second-tier molecular tests for patients with developmental disorders (DD), but the clinical utility of WGS continues to be debated. This prospective randomized trial involving all Belgian Human Genetics centers compared the standard of care (SoC) - combining WES and microarray or shallow WGS - with WGS for 567 individuals with unexplained DD. The diagnostic yield of WGS was 39.8% (113/284) vs 30% for SoC (85/283) (p=0.015), mainly due to an increased detection of single nucleotide variants and indels (+8.7%). WGS also enabled the detection of three non-coding (potential) pathogenic variants. Diagnostic yield was higher for females (45.5%, 97/213) compared to males (28.5%, 101/354) (p<0.001). De novo variants were found for 23.6% of patients. Analysis of inherited variants in genes associated with autosomal dominant phenotypes contributed more to the diagnostic yield (3.9%) than X-linked variants (1.9%), and to a similar extent as autosomal recessive variants (4.1%). This nationwide study demonstrates WGS outperforms WES for the diagnosis of patients with DD in a decentralized hospital setting and well-characterized cohort. The results also highlight the importance of evaluating autosomal dominant inherited variants in genomics analyses for DD.

  Study EGAS50000002018

• Distinct immune and genomic signatures predict resistance to ibrutinib therapy in Waldenström macroglobulinemia

  In this study, we investigate the complex interplay between tumour-acquired genetic features and the composition of the microenvironment in the promotion of ibrutinib resistance in WM patients by integrating single-cell RNA sequencing (scRNAseq) and whole-genome sequencing (WGS), to examine bone marrow tumour and immune compartments from 37 symptomatic WM patients treated with ibrutinib.

  Study EGAS50000001586

• Analysis File for 87 Argentinean individuals

  VCF for 87 Argentinean samples. Only SNPs (no indels) that passed the Affymetrix QC. Data from Luisi et al. 2020. Plos One. Fine-Scale Genomic Analyses Of Admixed Individuals Reveal Unrecognized Genetic Ancestry Components In Argentina. Reference Allele column does NOT contain reference allele from genome assembly.

  Dataset EGAD00001006227

• RNA-Sequencing and Somatic Mutation Status of Adrenocortical Tumors: Novel Pathogenetic Insights

  RNA paired end sequencing of 59 adrenocortical tumors and 4 controls.

  Dataset EGAD00001006258