DAC for "Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine"
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ABSTRACT:
PROVIDER: EGAC00001000419 | EGA |
REPOSITORIES: EGA
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Project description:The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. Whole genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilized WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counseling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.
| S-EPMC5447450 | biostudies-literature
Project description:The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. We compared diagnostic rate of WGS to CMA and targeted gene testing of 100 patients referred to The Hospital for Sick Children Genetics clinic in 2014. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In an additional 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling.
| EGAS00001001623 | EGA
Project description:Next-generation sequencing has revolutionized the molecular diagnosis of individuals affected by genetic kidney diseases. Indeed, rapid genetic testing in individuals with suspected inherited nephropathy has not only important implications for diagnosis and prognosis but also for genetic counseling. Nephronophthisis (NPHP) and related syndromes, a leading cause of end-stage renal failure, are autosomal recessive disorders characterized by the variable presentation and considerable locus heterogeneity with more than 90 genes described as single-gene causes. In this case report, we demonstrate the utility of whole-genome sequencing (WGS) for the molecular diagnosis of NPHP by identifying two putative disease-causing intronic mutations in the NPHP3 gene, including one deep intronic variant. We further show that both intronic variants, by affecting splicing, result in a truncated nephrocystin-3 protein. This study provides a framework for applying WGS as a first-line diagnostic tool for highly heterogeneous disease such as NPHP and further suggests that deep intronic variations are an important underestimated cause of monogenic disorders.
| S-EPMC7506526 | biostudies-literature
Project description:Rare diseases are usually chronically debilitating or even life-threatening with diagnostic and therapeutic challenges in current clinical practice. It has been estimated that 80% of rare diseases are genetic in origin, and thus genome sequencing-based diagnosis offers a promising alternative for rare-disease management. In this study, 79 individuals from 16 independent families were performed for whole-genome sequencing (WGS) in an effort to identify the causative mutations for 16 distinct rare diseases that are largely clinically intractable. Comprehensive analysis of variations, including simple nucleotide variants (SNVs), copy-number variations (CNVs), and structural variations (SVs), was implemented using the WGS data. A flexible analysis pipeline that allowed a certain degree of misclassification of disease status was developed to facilitate the identification of causative variants. As a result, disease-causing variants were identified in 10 of the 16 investigated diseases, yielding a diagnostic rate of 62.5%. Additionally, new potentially pathogenic variants were discovered for two disorders, including IGF2/INS-IGF2 in mitochondrial disease and FBN3 in Klippel-Trenaunay-Weber syndrome. Our WGS analysis not only detected a CNV associated with 3p deletion syndrome but also captured a simple sequence repeat (SSR) variation associated with Machado-Joseph disease. To our knowledge, this is the first time the clinical WGS analysis of short-read sequences has been used successfully to identify a causative SSR variation that perfectly segregates with a repeat expansion disorder. After the WGS analysis, we confirmed the initial diagnosis for three of 10 established disorders and modified or corrected the initial diagnosis for the remaining seven disorders. In summary, clinical WGS is a powerful tool for the diagnosis of rare diseases, and its diagnostic clarity at molecular levels offers important benefits for the participating families.
| S-EPMC6920370 | biostudies-literature
Project description:To assess their utility in routine neuropathology, we prospectively integrated DNA methylation-based CNS tumor classification and targeted gene panel sequencing of tumor and constitutional DNA with blinded neuropathological reference diagnostics for a population-based cohort of > 1,200 newly-diagnosed pediatric patients.
2023-01-30 | GSE215240 | GEO
Project description:Genomic profiling during the diagnosis of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification, and treatment decisions. Patients for whom diagnostic screening fails to identify disease-defining or risk-stratifying lesions are classified as having B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) of paired tumor-normal samples. For 52 patients with B-other, we compared the WGS findings with data from clinical and research cytogenetics. WGS identified a cancer-associated event in 51 of 52 patients, including an established subtype defining genetic alterations that were previously missed with standard-of-care (SoC) genetics in 5 of them. Of the 47 true B-other ALL, we identified a recurrent driver in 87% (41). A complex karyotype via cytogenetics emerges as a heterogeneous group, including distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r and IGK::BCL2). For a subset of 31 cases, we integrated the findings from RNA sequencing (RNA-seq) analysis to include fusion gene detection and classification based on gene expression. Compared with RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes; however, RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrated that WGS can identify clinically relevant genetic abnormalities missed with SoC testing as well as identify leukemia driver events in virtually all cases of B-other ALL.
| S-EPMC10405200 | biostudies-literature
Project description: Not available
| S-EPMC8563073 | biostudies-literature
Project description:Genome sequencing is now available as a clinical test on the National Health Service (NHS) through the Genome Medicine Service (GMS). The GMS have set out an analytical strategy that predominantly filters genome data on a pre-selected gene panel(s). Whilst this approach reduces the number of variants requiring assessment by reporting laboratories, pathogenic variants outside of the gene panel applied may be missed, and candidate variants in novel genes are largely ignored. This study sought to compare a research exome analysis to an independent clinical genome analysis performed through the NHS for the same group of patients. When analysing the exome data, we applied a panel agnostic approach filtering for variants with High Pathogenic Potential (HiPPo) using ClinVar, allele frequency, and in silico prediction tools. We then compared this gene agnostic analysis to the panel-based approach as applied by the GMS to genome data. Later we restricted HiPPo variants to a panel of the Gene Curation Coalition (GenCC) morbid genes and compared the diagnostic yield with the variants filtered using the GMS strategy. 24 patients from 8 families underwent parallel research exome sequencing and GMS genome sequencing. HiPPo analysis applied to research exome data identified a similar number of variants as the gene panel-based approach applied by the GMS. GMS clinical genome analysis identified and returned 2 pathogenic variants and 3 variants of uncertain significance. HiPPo research exome analysis identified the same variants plus an additional pathogenic variant and a further 3 de novo variants of uncertain significance in novel genes, where case series and functional studies are underway. When HiPPo was restricted to GenCC disease genes (strong or definitive), the same pathogenic variants were identified yet statistically fewer variants required assessment to identify more diagnostic variants than reported by the GMS genome strategy. This gave a diagnostic rate per variant assessed of 20% for HiPPo restricted to GenCC versus 3% for the GMS panel-based approach. With plans to sequence 5 million more NHS patients, strategies are needed to optimise the full potential of genome data beyond gene panels whilst minimising the burden of variants that require clinical assessment.
| S-EPMC9915838 | biostudies-literature
Project description:OBJECTIVES:Genetic disorders are a leading contributor to mortality in the neonatal ICU and PICU in the United States. Although individually rare, there are over 6,200 single-gene diseases, which may preclude a genetic diagnosis prior to ICU admission. Rapid whole genome sequencing is an emerging method of diagnosing genetic conditions in time to affect ICU management of neonates; however, its clinical utility has yet to be adequately demonstrated in critically ill children. This study evaluates next-generation sequencing in pediatric critical care. DESIGN:Retrospective cohort study. SETTING:Single-center PICU in a tertiary children's hospital. PATIENTS:Children 4 months to 18 years admitted to the PICU who were nominated between July 2016 and May 2018. INTERVENTIONS:Rapid whole genome sequencing with targeted phenotype-driven analysis was performed on patients and their parents, when parental samples were available. MEASUREMENTS AND MAIN RESULTS:A molecular diagnosis was made by rapid whole genome sequencing in 17 of 38 children (45%). In four of the 17 patients (24%), the genetic diagnoses led to a change in management while in the PICU, including genome-informed changes in pharmacotherapy and transition to palliative care. Nine of the 17 diagnosed children (53%) had no dysmorphic features or developmental delay. Eighty-two percent of diagnoses affected the clinical management of the patient and/or family after PICU discharge, including avoidance of biopsy, administration of factor replacement, and surveillance for disorder-related sequelae. CONCLUSIONS:This study demonstrates a retrospective evaluation for undiagnosed genetic disease in the PICU and clinical utility of rapid whole genome sequencing in a portion of critically ill children. Further studies are needed to identify PICU patients who will benefit from rapid whole genome sequencing early in PICU admission when the underlying etiology is unclear.
| S-EPMC6832787 | biostudies-literature
Project description:We report quantitation of specific mRNAs in two RNA samples isolated from normozoospermic whole semen
2013-11-23 | GSE52665 | GEO