NGS for diagnosing rare disorders
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB48104 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Histologic diagnosis of sellar masses can be challenging, particularly in rare neoplasms and tumors without definitive biomarkers. DNA methylation has recently emerged as a useful diagnostic tool. To illustrate the clinical utility of machine-learning-based DNA methylation classifiers, we report a rare case of primary sellar esthesioneuroblastoma diagnosed by DNA methylation classificiation but histologically mimicking a nonfunctioning pituitary adenoma.
2022-10-04 | GSE211634 | GEO
Project description:Patients with rare diseases often experience prolonged diagnostic delays. Ordering appropriate genetic tests is crucial yet challenging, especially for general pediatricians without genetic expertise. Recent American College of Medical Genetics (ACMG) guidelines embrace early use of exome sequencing (ES) or genome sequencing (GS) for conditions like congenital anomalies or developmental delays while still recommend gene panels for patients exhibiting strong manifestations of a specific disease. Recognizing the difficulty in navigating these options, we developed a machine learning model trained on 1005 patient records from Columbia University Irving Medical Center to recommend appropriate genetic tests based on the phenotype information. The model achieved a remarkable performance with an AUROC of 0.823 and AUPRC of 0.918, aligning closely with decisions made by genetic specialists, and demonstrated strong generalizability (AUROC:0.77, AUPRC: 0.816) in an external cohort, indicating its potential value for general pediatricians to expedite rare disease diagnosis by enhancing genetic test ordering.
| S-EPMC11582592 | biostudies-literature
Project description:Lysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders with variable degrees of severity and a broad phenotypic spectrum, which may overlap with a number of other conditions. While individually rare, as a group LSDs affect a significant number of patients, placing an important burden on affected individuals and their families but also on national health care systems worldwide. Here, we present our results on the use of an in-house customized next-generation sequencing (NGS) panel of genes related to lysosome function as a first-line molecular test for the diagnosis of LSDs. Ultimately, our goal is to provide a fast and effective tool to screen for virtually all LSDs in a single run, thus contributing to decrease the diagnostic odyssey, accelerating the time to diagnosis. Our study enrolled a group of 23 patients with variable degrees of clinical and/or biochemical suspicion of LSD. Briefly, NGS analysis data workflow, followed by segregation analysis allowed the characterization of approximately 41% of the analyzed patients and the identification of 10 different pathogenic variants, underlying nine LSDs. Importantly, four of those variants were novel, and, when applicable, their effect over protein structure was evaluated through in silico analysis. One of the novel pathogenic variants was identified in the GM2A gene, which is associated with an ultra-rare (or misdiagnosed) LSD, the AB variant of GM2 Gangliosidosis. Overall, this case series highlights not only the major advantages of NGS-based diagnostic approaches but also, to some extent, its limitations ultimately promoting a reflection on the role of targeted panels as a primary tool for the prompt characterization of LSD patients.
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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:Congenital diarrheal disorders (CDDs) are early-onset enteropathies generally inherited as autosomal recessive traits. Most patients with CDDs require rapid diagnosis as they need immediate and specific therapy to avoid a poor prognosis, but their clinical picture is often overlapping with a myriad of nongenetic diarrheal diseases. We developed a next-generation sequencing (NGS) panel for the analysis of 92 CDD-related genes, by which we analyzed patients suspect for CDD, among which were (i) three patients with sucrose-isomaltase deficiency; (ii) four patients with microvillous inclusion disease; (iii) five patients with congenital tufting enteropathy; (iv) eight patients with glucose-galactose malabsorption; (v) five patients with congenital chloride diarrhea. In all cases, we identified the mutations in the disease-gene, among which were several novel mutations for which we defined pathogenicity using a combination of bioinformatic tools. Although CDDs are rare, all together, they have an incidence of about 1%. Considering that the clinical picture of these disorders is often confusing, a CDD-related multigene NGS panel contributes to unequivocal and rapid diagnosis, which also reduces the need for invasive procedures.
| S-EPMC7915612 | biostudies-literature
Project description:BackgroundGenetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined.MethodsWe sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center.ResultsWe sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments.ConclusionsThe diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.).
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Project description:The demo datasets available for MSCohort analysis. You can download to inspect their formats and practice using the software tool. This dataset contains raw files of 7 urine QC samples, spectronaut analysis results and MSCohort report results
2024-03-06 | PXD050389 |
Project description:The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.
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