Expanding the genetic spectrum of Diamond-Blackfan anemia: novel mutations in RPS19, RPL5, and RPS10

New DBA cases identified with 3 novel frameshift mutations RPS19 (c.48_49del), RPL5 (c.9del), and RPS10 (c.268_275del), plus a known RPS26 nonsense variant (p.Arg28Ter). Distinct gene–phenotype correlations and treatment outcomes have been identified among 1,077 DBA patients; however, considerable overlap exists. Diamond-Blackfan anemia (DBA) is a rare congenital aplastic anemia syndrome characterized by the failure of red blood cell precursor production, mainly by mutations in ribosomal protein (RP) genes. While half of the patients exhibit congenital malformations, clear genotype-phenotype correlations remain elusive, highlighting the complexity of the diagnosis. Approximately 20% of DBA patients lack an identified mutation. Here, we describe five patients from four unrelated families carrying mutations in major RP genes. Three were novel frameshift variants: a 2-bp deletion in RPS19 (c.48_49del); a 1-bp deletion in RPL5 (c.9del) and an 8-bp deletion in RPS10 (c.268_275del). Additionally, we identified a nonsense variant in RPS26 (p.Arg28Ter) previously reported, but rare, in one of our patients. All variants are predicted to result in truncated proteins. To contextualize these findings, we performed a systematic analysis of RPS19, RPL5, RPS10 , and RPS26 mutations, uncovering over 450 unique variants across 1,077 patients, revealing gene-specific phenotypic patterns. RPL5 mutations were strongly associated with skeletal and craniofacial malformations, RPS19 with thumb anomalies, and RPS26 with craniofacial, skeletal and urogenital features. Our findings expand the mutational spectrum of DBA and strengthen evidence for gene-specific clinical signatures, offering a clearer framework for diagnosis and genotype-informed management.