Whole genome sequencing for novel neuromuscular disease gene discovery
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001004535 | EGA |
REPOSITORIES: EGA
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Project description:The Australian Acute Care Genomics program provides ultra-rapid diagnostic testing to critically ill infants and children with suspected genetic conditions. Over two years, we performed whole genome sequencing (WGS) in 290 families, with average time to result of 2.9 days, and diagnostic yield of 47%. We performed additional bioinformatic analyses and transcriptome sequencing in all patients who remained undiagnosed. Long-read sequencing and functional assays, ranging from clinically accredited enzyme analysis to bespoke quantitative proteomics, were deployed in selected cases. This resulted in an additional 19 diagnoses, and an overall diagnostic yield of 54%. Diagnostic variants ranged from structural chromosomal abnormalities through to an intronic retrotransposon, disrupting splicing. Critical care management changed in 120 diagnosed patients (77%). Results informed precision treatments; surgical and transplant decisions; and palliation in 94 (60%). We propose that integration of multi-omic approaches into mainstream diagnostic practice is necessary to realise the full potential of genomic testing.
2023-10-24 | PXD042001 | Pride
Project description:Guillain-Barré syndrome (GBS) is an immune-mediated peripheral neuropathy that debilitates the voluntary and autonomous response of the patient. In this study the transcriptome of peripheral blood mononuclear cells from a GBS patient and her healthy twin were compared to discover possible correlates of disease progression and recovery. Blood samples were collected simultaneously from the Guillain-Barré patient (A) and from her control healthy twin (B) at three different time points during disease progression from hospitalization in the intensive care unit (T1), passing to intermediate care (T2), and at conclusion of locomotion rehabilitation program when the patient was close to abandon the hospital (T3).
2015-09-05 | E-GEOD-72748 | biostudies-arrayexpress
Project description:Purpose: Selecting muscle-invasive bladder cancer patients for adjuvant therapy is currently based on clinical variables with limited power. We hypothesized that genomic-based signatures can outperform clinical models to identify patients at higher risk. Method:Transcriptome-wide expression profiles were generated using 1.4 million feature-arrays on archival tumors from 225 patients who underwent radical cystectomy and had muscle-invasive and/or node-positive bladder cancer. A 15-feature GC was developed on the discovery set with area under curve (AUC) of 0.77 in the validation set. A cohort comprised of 225 patients with organ-confined, muscle-invasive (pT2N0M0),extravesical (pT3-4aN0M0), and node-positive (pTanyN1-3M0) UCB who underwent radicalcystectomy at the University of Southern California between 1998 and 2004 was used. Each patient had aminimum two-year follow-up post-cystectomy unless they recurred prior to that date. Patients receiving neoadjuvant chemotherapy, and those with clinical evidence of lymphadenopathy or distant metastasis at diagnosis were excluded.
2014-10-27 | E-GEOD-57933 | biostudies-arrayexpress
Project description:Molecular classification of medulloblastoma is critical for the correct treatment of this malignant paediatric brain tumour. The analysis of genome-wide DNA methylation patterns has profoundly improved diagnostic precision and classification of brain tumours. However, the implementation of DNA methylation microarrays in daily clinical practice can be time-consuming, costly and inaccessible for many centres worldwide. We aimed to develop a machine-learning decision support system for rapid and cost-effective prediction of medulloblastoma methylation class directly from quantitative PCR data.
2023-08-23 | GSE210723 | GEO
Project description:In order to identify methylation changes in prostate cancer, we performed a genome-wide analysis of DNA methylation using Agilent human CpG island arrays. We then chose specific genes to validate methylation both in the same cases as were hybridized to the array (using quantitative EpiTYPER analysis) and in an independent series of prostate cancer samples (using MethyLight quantitative methylation specific PCR). We specifically chose low grade (Gleason score 6 cases) and high grade (Gleason score 8 cases) to discover methylated genes/loci that may be involved in the progression to a higher grade of prostate cancer. We collected 20 specimens consisting of 10 Gleason 6 and 10 Gleason 8 prostate cancers, and compared these to a reference lymphocyte pool (6 age matched, healthy men) to determine cancer associated methylation changes as well as disease progression associated methylation changes. We performed the differential methylation hybridization procedure as described by Yan et al. (Methods, 2002) on each case to enrich for methylated DNA. Each specimen in the reference pool underwent the same enrichment with amplicons being pooled at the end of the procedure. Each prostate cancer case was subsequently co-hybridized to the microarray with the reference pool.
2009-03-26 | E-GEOD-15298 | biostudies-arrayexpress
Project description:One unmet challenge in current lung cancer diagnosis is to accurately differentiate lung cancer patients from those with other lung diseases with similar clinical symptoms and radiological features. Previous studies have reported cases of misdiagnosis for patients with lung cancer mimicking pulmonary tuberculosis (TB) or for TB patients with multiple lung nodules mimicking lung cancer progression, which is concerning for clinical practice in TB-endemic countries/regions. Here, we develop a molecular signature composed of non-canonical small non-coding RNAs in human peripheral blood mononuclear cells (PBMCs), including tRNA-derived small RNAs (tsRNAs), rRNA-derived small RNAs (rsRNAs), and YRNA-derived small RNAs (ysRNAs). This signature consists of i) the tsRNAs derived from tRNA-Ala, tRNA-Asn, tRNA-Leu, tRNA-Lys, and tRNA-Tyr that are upregulated in the lung cancer patients relative to the healthy controls and patients with pulmonary TB, ii) the rsRNAs derived from rRNA-5S that are upregulated in the lung cancer patients but downregulated in TB patients relative to the controls, and iii) the ysRNAs originating from YRNA-RNY1 that are downregulated in the lung cancer patients but upregulated in the TB patients compared with the controls. This diagnostic signature discriminates between healthy controls, lung cancer patients, and pulmonary TB subjects with high accuracy in both the discovery and validation cohorts. We conclude that the PBMC tsRNAs, rsRNAs, and ysRNAs are informative for both screening for and discriminating between lung cancer and pulmonary TB.
2020-11-16 | GSE148861 | GEO
Project description:BackgroundTo date, few peptides in the complex mixture of platypus venom have been identified and sequenced, in part due to the limited amounts of platypus venom available to study. We have constructed and sequenced a cDNA library from an active platypus venom gland to identify the remaining components.ResultsWe identified 83 novel putative platypus venom genes from 13 toxin families, which are homologous to known toxins from a wide range of vertebrates (fish, reptiles, insectivores) and invertebrates (spiders, sea anemones, starfish). A number of these are expressed in tissues other than the venom gland, and at least three of these families (those with homology to toxins from distant invertebrates) may play non-toxin roles. Thus, further functional testing is required to confirm venom activity. However, the presence of similar putative toxins in such widely divergent species provides further evidence for the hypothesis that there are certain protein families that are selected preferentially during evolution to become venom peptides. We have also used homology with known proteins to speculate on the contributions of each venom component to the symptoms of platypus envenomation.ConclusionsThis study represents a step towards fully characterizing the first mammal venom transcriptome. We have found similarities between putative platypus toxins and those of a number of unrelated species, providing insight into the evolution of mammalian venom.
| S-EPMC2965387 | biostudies-literature
Project description:In current clinical practice care of diseased patients is often restricted to separated disciplines. However, such an organ-centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients. Moreover, these patients have an increased risk for age-associated dementias. The underlying molecular mechanisms are presently unknown and thus corresponding therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model organisms we show that heart failure leads to specific changes in hippocampal gene-expression, a brain region intimately linked to cognition. These changes reflect increased cellular stress pathways which eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory function. These pathological changes are ameliorated via the administration of a drug that promotes neuronal euchromatin formation. Our study provides first insight to the molecular processes by which heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive defects in heart failure patients.
2020-12-01 | GSE159445 | GEO
Project description:In current clinical practice care of diseased patients is often restricted to separated disciplines. However, such an organ-centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients. Moreover, these patients have an increased risk for age-associated dementias. The underlying molecular mechanisms are presently unknown and thus corresponding therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model organisms we show that heart failure leads to specific changes in hippocampal gene-expression, a brain region intimately linked to cognition. These changes reflect increased cellular stress pathways which eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory function. These pathological changes are ameliorated via the administration of a drug that promotes neuronal euchromatin formation. Our study provides first insight to the molecular processes by which heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive defects in heart failure patients.
2020-12-01 | GSE159443 | GEO
Project description:In current clinical practice care of diseased patients is often restricted to separated disciplines. However, such an organ-centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients. Moreover, these patients have an increased risk for age-associated dementias. The underlying molecular mechanisms are presently unknown and thus corresponding therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model organisms we show that heart failure leads to specific changes in hippocampal gene-expression, a brain region intimately linked to cognition. These changes reflect increased cellular stress pathways which eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory function. These pathological changes are ameliorated via the administration of a drug that promotes neuronal euchromatin formation. Our study provides first insight to the molecular processes by which heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive defects in heart failure patients.
2020-12-01 | GSE159442 | GEO