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Title: Utility of clinical comprehensive genomic characterisation for diagnostic categorisation in patients presenting with hypocellular bone marrow failure syndromes.
Austin Authors: Blombery, Piers;Fox, Lucy;Ryland, Georgina L;Thompson, Ella R;Lickiss, Jennifer;McBean, Michelle;Yerneni, Satwica;Hughes, David;Greenway, Anthea;Mechinaud, Francoise;Wood, Erica M;Lieschke, Graham J;Szer, Jeff;Barbaro, Pasquale;Roy, John;Wight, Joel C ;Lynch, Elly;Martyn, Melissa;Gaff, Clara;Ritchie, David
Affiliation: University of Melbourne, Peter MacCallum Cancer Centre, Melbourne, Australia
Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
Clinical Haematology, Peter MacCallum Cancer Centre/Royal Melbourne Hospital, Melbourne, Australia
Melbourne Genomics Health Alliance, Parkville VIC, Australia
Department of Haematology, Austin Health, Heidelberg, Victoria, Australia
Children Health Queensland and University of Queensland, South Brisbane QLD, Australia
Transfusion Research Unit, Monash University, Melbourne, Australia
Royal Children's Hospital, Melbourne, Australia
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia
Issue Date: 1-Jan-2021
Date: 2020-02-13
Publication information: Haematologica 2021; 106(1): 64-73
Abstract: Bone marrow failure (BMF) related to hypoplasia of haematopoietic elements in the bone marrow is a heterogeneous clinical entity with a broad differential diagnosis including both inherited and acquired causes. Accurate diagnostic categorisation 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 characterisation 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 characterisation 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 categorisation 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 characterisation can improve diagnostic categorisation of patients presenting with hypoplastic BMF syndromes and should be routinely performed in this group of patients.
DOI: 10.3324/haematol.2019.237693
Journal: Haematologica
PubMed URL: 32054657
Type: Journal Article
Subjects: Bone Marrow Failure
Cytogenetics and Molecular Genetics
Myelodysplastic Syndromes
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