Diamond-Blackfan anemia: Report of seven further mutations in the RPS19 gene and evidence of mutation heterogeneity in the Italian population

Diamond-Blackfan anemia (DBA) is a congenital disease characterized by defe ctive erythroid progenitor maturation and physical malformations. Most case s are sporadic, but dominant or, more rarely, recessive inheritance is obse rved in 10% of patients. Mutations in the gene encoding ribosomal protein ( RP) S19 have recently been found in 25% of patients with either the dominan t or the sporadic form. DBA is the first human disease due to mutations in a ribosomal structural protein. Families unlinked to this locus have also b een reported, In an investigation of 23 individuals, we identified eight di fferent mutations in 9 patients. These include five missense, one frameshif t, one splice site defect, and one 4-bp insertion in the regulatory sequenc e, Seven mutations are new; one has so far been found in 8 patients and is a relatively common de novo event. Two mutations are predicted to generate a truncated protein. We also report the prevalence of RPS 19 mutations in t he Italian DBA population, as shown by an analysis of 56 patients, No genot ype-phenotype correlation was found between patients with the same mutation . The main clinical applications for molecular analysis are clinical diagno sis of patients with an incomplete form of DBA and testing of siblings of a patient with a severe form so as to avoid using those who carry a mutation and a silent phenotype as allogeneic stem cell donors. (C) 2000 Academic P ress.