title: Ribosomal protein gene deletions in Diamond-Blackfan anemia.
abstract: Diamond-Blackfan anemia (DBA) is a congenital BM failure syndrome characterized by hypoproliferative anemia, associated physical abnormalities, and a predisposition to cancer. Perturbations of the ribosome appear to be critically important in DBA; alterations in 9 different ribosomal protein genes have been identified in multiple unrelated families, along with rarer abnormalities of additional ribosomal proteins. However, at present, only 50% to 60% of patients have an identifiable genetic lesion by ribosomal protein gene sequencing. Using genome-wide single-nucleotide polymorphism array to evaluate for regions of recurrent copy variation, we identified deletions at known DBA-related ribosomal protein gene loci in 17% (9 of 51) of patients without an identifiable mutation, including RPS19, RPS17, RPS26, and RPL35A. No recurrent regions of copy variation at novel loci were identified. Because RPS17 is a duplicated gene with 4 copies in a diploid genome, we demonstrate haploinsufficient RPS17 expression and a small subunit ribosomal RNA processing abnormality in patients harboring RPS17 deletions. Finally, we report the novel identification of variable mosaic loss involving known DBA gene regions in 3 patients from 2 kindreds. These data suggest that ribosomal protein gene deletion is more common than previously suspected and should be considered a component of the initial genetic evaluation in cases of suspected DBA.
authors: Division of Pediatric Oncology, Department of Oncology, Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. jfarrar4@jhmi.edu
authors: Jason E
authors: JE
authors: Farrar
authors: Adrianna
authors: A
authors: Vlachos
authors: Eva
authors: E
authors: Atsidaftos
authors: Hannah
authors: H
authors: Carlson-Donohoe
authors: Thomas C
authors: TC
authors: Markello
authors: Robert J
authors: RJ
authors: Arceci
authors: Steven R
authors: SR
authors: Ellis
authors: Jeffrey M
authors: JM
authors: Lipton
authors: David M
authors: DM
authors: Bodine
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000235:genetics*; D015152:Blotting, Northern; D002675:Child, Preschool; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study / Q000379:methods; D060005:Genotyping Techniques / Q000379:methods; D057895:Haploinsufficiency; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000235:genetics*
chemical_list: C489281:RPL35A protein, human; C489203:RPS26 protein, human; D012269:Ribosomal Proteins; C037084:ribosomal protein S17; C040343:ribosomal protein S19