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A Comprehensive Whole Genome Sequencing Assay Provides Robust Characterization of Clinically Relevant Genomic Alterations across Myeloid Malignancies Concordant with Matched Results from Targeted DNA, Whole Transcriptome RNA and Cytogenetic Profiling
Through a pilot study, we assess the performance of the WGS profiling assay in 135 patients with AML, MDS, CML
We demonstrate high concordance (>98.9%) in identifying guideline recommended genomic alterations, including large CNAs, in myeloid malignancies by a single WGS test compared to parallel conventional methods.
The ability to obtain large CNA results, historically reserved for cytogenetic testing, has the potential to save costs and fill an unmet clinical need globally where cytogenetic resources are limited.
ASH Volume 144, Issue Supplement 1 2024
Development and Validation of an NGS Assay for the Detection Of Clinically Actionable Genetic Variants in DPYD and UGT1A1
Dual-purpose NGS Data: Enables DPYD and UGT1A1 genotyping from tumor profiling NGS data, aiding in identifying potential chemotherapy adverse reactions alongside therapy selection.
High-Accuracy Assay: Uses DeepVariant software and a novel algorithm for TA repeats, validated with 100% accuracy in 199 samples through orthogonal methods like Sanger sequencing.
Clinical Impact: Facilitates personalized cancer treatment by accurately detecting genetic variants linked to adverse reactions to drugs like 5-FU and irinotecan, ensuring safer therapy decisions.
The work was featured on the cover of Neurology
DNM1 encephalopathy: A new disease of vesicle fission.
The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies.
Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date.
Given the predicted dominant-negative mechanism of this mutation, patients with this variant presents a prime target for therapeutic discovery and intervention.
The landscape of somatic mutations in epigenetic regulators across 1000 pediatric cancer genomes.
To define the landscape of somatic mutations in epigenetic regulators in pediatric cancer, we identified 633 genes that bind, modify or establish complexes on a histone peptide, reorganize nucleosomes, or modify or bind modified genomic DNA.
The exons from the 633 genes were sequenced in 21 pediatric cancers from 1023 paired tumors.
Novel SNVs in the deubiquitinase USP7 were uncovered in T-cell acute lymphoblastic leukemia. Cellular assays on two mutations, C300R and D305G, correlated with a decrease in the deubiquitination of its target H2B ubiquityl Lys120. These loss-of-function mutations occur at the binding interface between the USP7 and ubiquitin.
Sequence Fingerprint and Structural Analysis of the A3DFK9 SCOR Enzyme from Clostridium thermocellum.
The SCOR protein from industrial important bacterium C. thermocellum contains a Cys84 in a highly conserved Gly84 and a Gly106 in a highly conserved Asn106 position.
The structure revealed the N-G and G-C double variation is critical because the mutation of G84 to C84 would clash with the A103. The presence of any other residue besides Gly in the Asn position would sterically be prohibited (PDB:3GED [Green] and PDB:1HDC [Teal]). Further, the C84 could not coordinating the water wire and proton release to bulk solvent. However, there is a direct line of water molecules <3.5A from the catalytic Lys through the protein.
Interestingly, as a breaker in the helix, Pro110 influences G106 carbonyl, making it available to hydrogen bond explaining the amino acid switch and retention of the “water wire” important for connecting the catalytic site to bulk solvent.
The short chain oxidoreductase Q9HYA2 from Pseudomonas aeruginosa PAO1 contains an atypical catalytic center.
We identified a SCOR protein with an atypical catalytic center of Arg-Ser-Thr in the bacterium Pseudomonas aeruginosa. This atypical catalytic center and their operons were identified in 86 additional bacterial species (left image) .
Structural alignment to a a typical SCOR, polyketide ketoreductase (KR), demonstrated that Q9HYA2’s Ser146 and Arg163 superimposed upon the KR’s catalytic Ser144 and Lys161, respectively (right image).
A chloride ion is bound at the position normally occupied by the catalytic tyrosine hydroxyl. The putative active site of Q9HYA2 contains a chemical moiety at each catalytically important position of a typical SCOR enzyme.
Robert Huether
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