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 (p=0.0006), developmental delay (p=0.006) and short stature (p=0.04) compared to nucleotide-level mutations. In conclusion, a significant proportion of patients with IBMFSs harbor pathogenic CNVs which were associated with a more extensive non-hematological phenotype in this cohort. Patients with a phenotype suggestive of IBMFSs but without identification of pathogenic nucleotide-level mutations should undergo specific testing for CNVs.
Keywords: Biological sciences/Biological techniques/Genomic analysis/Comparative genomic hybridization; Biological sciences/Biological techniques/High-throughput screening; Biological sciences/Cancer/Paediatric cancer; Biological sciences/Genetics/Clinical genetics/Genetic testing; Biological sciences/Genetics/Genotype/Genetic predisposition to disease.