Diamond-Blackfan anemia: genotype-phenotype correlation in Italian patients with RPL5 and RPL11 mutations

Background Diamond-Blackfan anemia (DBA) is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors. About 40% of patients display malformations. Anemia is corrected by steroid treatment in more than 50% of cases; non-responders need chronic transfusions or stem cell transplantation. Defects in the RPS19 gene, encoding the ribosomal protein (RP) S19, are the main known cause of DBA, and account for more than 25% of patients. Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that DBA is a disorder of ribosome biogenesis. Gadza et al. and Cmejla et al. have reported involvement of two new genes (RPL5, RPL11) encoding for RPs of the large subunit in a considerable percentage of DBA patients. DESIGN AND METHODS: Here we report the screening of coding sequence and intron-exon boundaries of RPS14, RPS16, RPS24, RPL5, RPL11, and RPL35A in 92 Italian patients negative for RPS19 mutations. RESULTS: About 20% displayed mutations in RPL5 or RPL11, and only 1.6% in RPS24. All but three mutations that we report here are new mutations. No mutations were found in RPS14, RPS16, and RPL35A. Remarkably, we observed a higher percentage of somatic malformations in RPL5 and RPL11 patients. A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations. Conclusions Mutations in four RPs account for around 50% of all Italian DBA patients. Genotype-phenotype data suggest that mutation screening should begin with RPL5 and RPL11 in DBA patients with a malformative status.