Reanalysing genomic data by normalized coverage values uncovers CNVs in bone marrow failure gene panels.

Autor:	Lauhasurayotin S; 1Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON Canada.; 2Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON Canada., Cuvelier GD; 3Pediatric Hematology-Oncology-Bone Marrow Transplantation, University of Manitoba, Cancer Care Manitoba, Winnipeg, MB Canada., Klaassen RJ; 4Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON Canada., Fernandez CV; 5Pediatric Hematology/Oncology, IWK Health Centre, Halifax, NS Canada., Pastore YD; 6CHU Sainte-Justine, Montreal, QC Canada., Abish S; 7Pediatric Hematology Oncology, Montreal Children's Hospital, Montreal, QC Canada., Rayar M; 8Division of Hematology/Oncology, UBC & B.C. Children's Hospital, Vancouver, BC Canada., Steele M; 9Alberta Children's Hospital, Calgary, Canada., Jardine L; 10Children's Hospital, London Health Sciences Centre, London, ON Canada., Breakey VR; 11Department of Pediatrics, McMaster University, Hamilton, ON Canada., Brossard J; 12Centre hospitalier universitaire, Sherbrooke, QC Canada., Sinha R; 13Royal University Hospital, Saskatoon, SK Canada., Silva M; 14Kingston General Hospital, Kingston, ON Canada., Goodyear L; 15Pediatric Hematology/Oncology, Janeway Child Health Centre, St. John's, NF Canada., Lipton JH; 16Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON Canada., Michon B; 17Centre Hospitalier Universitaire de Quebec, Sainte-Foy, QC Canada., Corriveau-Bourque C; 18Pediatrics, University of Alberta, Edmonton, AB Canada., Sung L; 19Population Health Sciences, Research Institute, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON Canada., Shabanova I; 1Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON Canada., Li H; 1Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON Canada., Zlateska B; 1Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON Canada., Dhanraj S; 1Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON Canada.; 20Institute of Medical Science, University of Toronto, Toronto, ON Canada., Cada M; 2Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON Canada., Scherer SW; 1Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON Canada.; 21McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, ON Canada., Dror Y; 1Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON Canada.; 2Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON Canada.; 20Institute of Medical Science, University of Toronto, Toronto, ON Canada.
Jazyk:	angličtina
Zdroj:	NPJ genomic medicine [NPJ Genom Med] 2019 Dec 09; Vol. 4, pp. 30. Date of Electronic Publication: 2019 Dec 09 (Print Publication: 2019).
DOI:	10.1038/s41525-019-0104-9
Abstrakt:	Inherited bone marrow failure syndromes (IBMFSs) are genetically heterogeneous disorders with cytopenia. Many IBMFSs also feature physical malformations and an increased risk of cancer. Point mutations can be identified in about half of patients. Copy number variation (CNVs) have been reported; however, the frequency and spectrum of CNVs are unknown. Unfortunately, current genome-wide methods have major limitations since they may miss small CNVs or may have low sensitivity due to low read depths. Herein, we aimed to determine whether reanalysis of NGS panel data by normalized coverage value could identify CNVs and characterize them. To address this aim, DNA from IBMFS patients was analyzed by a NGS panel assay of known IBMFS genes. After analysis for point mutations, heterozygous and homozygous CNVs were searched by normalized read coverage ratios and specific thresholds. Of the 258 tested patients, 91 were found to have pathogenic point variants. NGS sample data from 165 patients without pathogenic point mutations were re-analyzed for CNVs; 10 patients were found to have deletions. Diamond Blackfan anemia genes most commonly exhibited heterozygous deletions, and included RPS19 , RPL11 , and RPL5 . A diagnosis of GATA2 -related disorder was made in a patient with myelodysplastic syndrome who was found to have a heterozygous GATA2 deletion. Importantly, homozygous FANCA deletion were detected in a patient who could not be previously assigned a specific syndromic diagnosis. Lastly, we identified compound heterozygousity for deletions and pathogenic point variants in RBM8A and PARN genes. All deletions were validated by orthogonal methods. We conclude that careful analysis of normalized coverage values can detect CNVs in NGS panels and should be considered as a standard practice prior to do further investigations. Competing Interests: Competing interestsThe authors declare no competing interests. (© The Author(s) 2019.)
Databáze:	MEDLINE
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