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Diamond-Blackfan anemia (DBA) features hypoplastic anemia and congenital malformations, largely caused by mutations in various ribosomal proteins. The aim of this study was to characterize the spectrum of genetic lesions causing DBA and identify genotypes that correlate with phenotypes of clinical significance. Seventy-four patients with DBA from across Canada were included. Nucleotide-level mutations or large deletions were identified in 10 ribosomal genes in 45 cases. The RPS19 mutation group was associated with higher requirement for chronic treatment for anemia than other DBA groups. Patients with RPS19 mutations, however, were more likely to maintain long-term corticosteroid response without requirement for further chronic transfusions. Conversely, patients with RPL11 mutations were less likely to need chronic treatment. Birth defects, including cardiac, skeletal, hand, cleft lip or palate and genitourinary malformations, also varied among the various genetic groups. Patients with RPS19 mutations had the fewest number of defects, while patients with RPL5 had the greatest number of birth defects. This is the first study to show differences between DBA genetic groups with regards to treatment. Previously unreported differences in the rate and types of birth defects were also identified. These data allow better patient counseling, a more personalized monitoring plan, and may also suggest differential functions of DBA genes on ribosome and extra-ribosomal functions.

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., Blood disorders: impact of genomic structural variation Copy number variation in patients with inherited bone marrow failure syndromes (IBMFSs) is associated with more severe clinical symptoms. In addition to persistently low levels of red blood cells, white blood cells and/ or platelets, patients with IBMFSs also present varying degrees of physical malformations. Most cases are associated with single base-pair mutations in the DNA sequence, but Canadian researchers led by Yigal Dror at The Hospital for Sick Children in Toronto, have found that whole sections of the genome are deleted or repeated in an important proportion of patients. Those carrying copy number variants (CNV) presented more commonly with developmental delay, short stature and defects in more organ systems, than patients with point mutations. CNV analysis of patients with suspected IBMFSs could aid early disease evaluation and management.

There is an Inside Blood Commentary on this article in this issue.