ORCID Profile
0000-0003-3709-842X
Current Organisations
Peter MacCallum Cancer Centre
,
Vellore Institute of Technology University
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Publisher: Springer Science and Business Media LLC
Date: 20-03-2017
Publisher: Elsevier BV
Date: 09-2020
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 13-02-2021
DOI: 10.3324/HAEMATOL.2019.237693
Abstract: Bone marrow failure (BMF) related to hypoplasia of hematopoietic elements in the bone marrow is a heterogeneous clinical entity with a broad differential diagnosis including both inherited and acquired causes. Accurate diagnostic categorization is critical to optimal patient care and detection of genomic variants in these patients may provide this important diagnostic and prognostic information. We performed real-time, accredited (ISO15189) comprehensive genomic characterization including targeted sequencing and whole exome sequencing in 115 patients with BMF syndrome (median age 24 years, range 3 months - 81 years). In patients with clinical diagnoses of inherited BMF syndromes, acquired BMF syndromes or clinically unclassifiable BMF we detected variants in 52% (12/23), 53% (25/47) and 56% (25/45) respectively. Genomic characterization resulted in a change of diagnosis in 30/115 (26%) including the identification of germline causes for 3/47 and 16/45 cases with pre-test diagnoses of acquired and clinically unclassifiable BMF respectively. The observed clinical impact of accurate diagnostic categorization included choice to perform allogeneic stem cell transplantation, disease-specific targeted treatments, identification of at-risk family members and influence of sibling allogeneic stem cell donor choice. Multiple novel pathogenic variants and copy number changes were identified in our cohort including in TERT, FANCA, RPS7 and SAMD9. Whole exome sequence analysis facilitated the identification of variants in two genes not typically associated with a primary clinical manifestation of BMF but also demonstrated reduced sensitivity for detecting low level acquired variants. In conclusion, genomic characterization can improve diagnostic categorization of patients presenting with hypoplastic BMF syndromes and should be routinely performed in this group of patients.
Publisher: The Company of Biologists
Date: 07-2021
DOI: 10.1242/DMM.047431
Abstract: Zebrafish are an important model for studying phagocyte function, but rigorous experimental systems to distinguish whether phagocyte-dependent effects are neutrophil or macrophage specific have been lacking. We have developed and validated transgenic lines that enable superior demonstration of cell-autonomous neutrophil and macrophage genetic requirements. We coupled well-characterized neutrophil- and macrophage-specific Gal4 driver lines with UAS:Cas9 transgenes for selective expression of Cas9 in either neutrophils or macrophages. Efficient gene editing, confirmed by both Sanger and next-generation sequencing, occurred in both lineages following microinjection of efficacious synthetic guide RNAs into zebrafish embryos. In proof-of-principle experiments, we demonstrated molecular and/or functional evidence of on-target gene editing for several genes (mCherry, lamin B receptor, trim33) in either neutrophils or macrophages as intended. These new UAS:Cas9 tools provide an improved resource for assessing in idual contributions of neutrophil- and macrophage-expressed genes to the many physiological processes and diseases modelled in zebrafish. Furthermore, this gene-editing functionality can be exploited in any cell lineage for which a lineage-specific Gal4 driver is available. This article has an associated First Person interview with the first author of the paper.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 07-2015
Publisher: Elsevier BV
Date: 04-2014
Publisher: Springer Science and Business Media LLC
Date: 23-06-2020
DOI: 10.1038/S41598-020-67205-0
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Elsevier BV
Date: 08-2021
Publisher: American Society of Hematology
Date: 17-09-2015
DOI: 10.1182/BLOOD-2014-12-616169
Abstract: RhoA GTPase activates pMRLC and localizes to the site of midbody formation to regulate erythroblast cytokinesis. Cytokinesis failure in erythroblasts caused by RhoA deficiency triggers p53-mediated DNA-damage response, cell-cycle arrest, and apoptosis.
Publisher: Springer Science and Business Media LLC
Date: 23-04-2019
DOI: 10.1038/S41598-019-42858-8
Abstract: Next Generation Sequencing is now routinely used in the practice of diagnostic pathology to detect clinically relevant somatic and germline sequence variations in patient s les. However, clinical assessment of copy number variations (CNVs) and large-scale structural variations (SVs) is still challenging. While tools exist to estimate both, their results are typically presented separately in tables or static plots which can be difficult to read and are unable to show the context needed for clinical interpretation and reporting. We have addressed this problem with CNspector, a multi-scale interactive browser that shows CNVs in the context of other relevant genomic features to enable fast and effective clinical reporting. We illustrate the utility of CNspector at different genomic scales across a variety of s le types in a range of case studies. We show how CNspector can be used for diagnosis and reporting of exon-level deletions, focal gene-level lifications, chromosome and chromosome arm level lifications/deletions and in complex genomic rearrangements. CNspector is a web-based clinical variant browser tailored to the clinical application of next generation sequencing for CNV assessment. We have demonstrated the utility of this interactive software in typical applications across a range of tissue types and disease contexts encountered in the context of diagnostic pathology. CNspector is written in R and the source code is available for download under the GPL3 Licence from github.com/PapenfussLab/CNspector .
No related grants have been discovered for satwica yerneni.