The clinical impact of copy number variants in inherited bone marrow failure syndromes

Inherited bone marrow failure syndromes comprise a genetically heterogeneous group of diseases with hematopoietic failure and a wide array of physical malformations. Copy number variants were reported in some inherited bone marrow failure syndromes. It is unclear what impact copy number variants play in patients evaluated for a suspected diagnosis of inherited bone marrow failure syndromes. 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 copy number variants (at least 1 kilobasepairs) were compared to cases with other mutations. Genotype-phenotype correlations were performed to assess the impact of copy number variants. Pathogenic nucleotide-level mutations were found in 157 of 303 tested patients (51.8%). Genome-wide copy number variant analysis by single-nucleotide polymorphism arrays or comparative genomic hybridization arrays revealed pathogenic copy number variants in 11 of 67 patients tested (16.4%). In four of these patients, identification of copy number variant was crucial for establishing the correct diagnosis as their clinical presentation was ambiguous. Eight additional patients were identified to harbor pathogenic copy number variants by other methods. Of the 19 patients with pathogenic copy number variants, four had compound-heterozygosity of a copy number variant with a nucleotide-level mutation. Pathogenic copy number variants 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 inherited bone marrow failure syndromes harbor pathogenic copy number variants which were associated with a more extensive non-hematological phenotype in this cohort. Patients with a phenotype suggestive of inherited bone marrow failure syndromes but without identification of pathogenic nucleotide-level mutations should undergo specific testing for copy number variants.