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The diagnostic utility of somatic mutations in the context of cytopenias is unclear: clonal hematopoiesis can be found in healthy individuals, patients with aplastic anemia (AA), clonal cytopenia of undetermined significance (CCUS) and myelodysplastic syndrome (MDS). We examined a cohort of 207 well-characterized cytopenic patients with a 640-gene next generation sequencing (NGS) panel and compared its diagnostic utility with a "virtual" 41 gene panel. TET2, SF3B1, ASXL1, and TP53 were the most commonly mutated genes (frequency>10%). Mutations in the 640 gene panel show high sensitivity (98.3%) but low specificity (47.6%) for diagnosis of MDS. Notably, mutations of splicing factors and genes in the RAS pathway are relatively specific to MDS. Furthermore, high variant allele frequency (VAF) predicts
when the VAF is set at 20% the positive predictive value (PPV) for MDS is 95.9% with a specificity of 95.3%. Presence of two or more somatic mutations with ≥10% VAF showed a PPV of 95.2%. While the "virtual" 41 gene panel showed a mild decrease in sensitivity (95.7% vs. 98.3%), 100% specificity was observed when either VAF was set at ≥20% (100% vs. 95.3%) or two or more somatic mutations had VAFs ≥10%. Our study shows targeted gene panel sequencing improves the diagnostic approach and accuracy for unexplained cytopenia with its high sensitivity and high PPV for MDS when applying VAF cutoffs; furthermore, a 41-gene panel was shown to have at least comparable performance characteristics to the large 640-gene panel. This article is protected by copyright. All rights reserved.
This article was published in the following journal.
Name: American journal of hematology
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The audibility limit of discriminating sound intensity and pitch.
Techniques of nucleotide sequence analysis that increase the range, complexity, sensitivity, and accuracy of results by greatly increasing the scale of operations and thus the number of nucleotides, and the number of copies of each nucleotide sequenced. The sequencing may be done by analysis of the synthesis or ligation products, hybridization to preexisting sequences, etc.
A technique which uses synthetic oligonucleotides to direct the cell's inherent DNA repair system to correct a mutation at a specific site in an episome or chromosome.
Direct nucleotide sequencing of gene fragments from multiple housekeeping genes for the purpose of phylogenetic analysis, organism identification, and typing of species, strain, serovar, or other distinguishable phylogenetic level.
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