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

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

Diagnostic algorithm for lower-risk myelodysplastic syndromes

Rapid advances over the past decade have uncovered the heterogeneous genomic and immunologic landscape of myelodysplastic syndromes (MDS). This has led to notable improvements in the accuracy and timing of diagnosis and prognostication of MDS, as well as the identification of possible novel targets for therapeutic intervention. For the practicing clinician, however, this increase in genomic, epigenomic, and immunologic knowledge needs consideration in a “real-world” context to aid diagnostic specificity. Although the 2016 revision to the World Health Organization classification for MDS is comprehensive and timely, certain limitations still exist for day-to-day clinical practice. In this review, we describe an up-to-date diagnostic approach to patients with suspected lower-risk MDS, including hypoplastic MDS, and demonstrate the requirement for an “integrated” diagnostic approach. Moreover, in the era of rapid access to massive parallel sequencing platforms for mutational screening, we suggest which patients should undergo such analyses, when such screening should be performed, and how those data should be interpreted. This is particularly relevant given the recent findings describing age-related clonal hematopoiesis