The Clinical Impact of Copy Number Variants in Inherited Bone Marrow Failure Syndromes

Authors

Nicolas Waespe, The Hospital for Sick Children
Santhosh Dhanraj, The Hospital for Sick Children
Manju Wahala, The Hospital for Sick Children
Elena Tsangaris, The Hospital for Sick Children
Tom Enbar, The Hospital for Sick Children
Bozana Zlateska, University of Toronto
Hongbing Li, University of Toronto
Robert J Klaassen, Children's Hospital of Eastern Ontario
Conrad V Fernandez, IWK Health Centre
Geoff D E Cuvelier, University of Manitoba
John K Wu, UBC & B.C. Children's Hospital
Yves D Pastore, CHU Sainte-Justine
Mariana Silva, Kingston General Hospital
Jeffrey H Lipton, University of Toronto
Joseé Brossard, Centre Hospitalier Universitaire
Bruno Michon, Centre Hospitalier Universitaire, Quebec
Sharon Abish, Montreal Children's Hospital
MacGregor Steele, Alberta Children's Hospital
Roona Sinha, Royal University Hospital
Mark J Belletrutti, University of Alberta
Vicky R Breakey, McMaster University
Lawrence Jardine, Western University
Lisa Goodyear, Janeway Child Health Centre
Liat Kofler, The Hospital for Sick Children
Michaela Cada, University of Toronto
Lillian Sung, The Hospital for Sick Children
Mary Shago, The Hospital for Sick Children
Stephen W Scherer, The Hospital for Sick Children
Yigal Dror, University of Toronto

Document Type

Article

Publication Date

5-10-2017

Journal

Nature Partner Journals

Volume

2

URL with Digital Object Identifier

https://doi.org/10.1038/s41525-017-0019-2

Abstract

Inherited bone marrow failure syndromes (IBMFSs) comprise a genetically heterogeneous group of diseases with hematopoietic failure and a wide array of physical malformations. Copy number variants (CNVs) were reported in some IBMFSs. It is unclear what impact CNVs play in patients evaluated for a suspected diagnosis of IBMFS. Clinical and genetic data of 323 patients from the Canadian Inherited Marrow Failure Registry from 2001 to 2014, who had a documented genetic work-up, were analyzed. Cases with pathogenic CNVs (at least 1 kilobasepairs) were compared to cases with other mutations. Genotype-phenotype correlations were performed to assess the impact of CNVs. Pathogenic nucleotide-level mutations were found in 157 of 303 tested patients (51.8%). Genome-wide CNV analysis by single nucleotide polymorphism arrays or comparative genomic hybridization arrays revealed pathogenic CNVs in 11 of 67 patients tested (16.4%). In four of these patients, identification of CNV was crucial for establishing the correct diagnosis as their clinical presentation was ambiguous. Eight additional patients were identified to harbor pathogenic CNVs by other methods. Of the 19 patients with pathogenic CNVs, four had compound-heterozygosity of a CNV with a nucleotide-level mutation. Pathogenic CNVs were associated with more extensive non-hematological organ system involvement (

Notes

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