Are Associated with Cleft Palate and Abnormal Thumbs in Diamond-Blackfan Anemia Patients

Diamond-Blackfan anemia (DBA), a congenital bone-marrow-failure syndrome, is characterized by red blood cell aplasia, macrocytic anemia, clinical heterogeneity, and increased risk of malignancy. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital anomalies that are present in ~30%–50% of patients. The disease has been associated with mutations in four ribosomal protein (RP) genes, RPS19, RPS24, RPS17, and RPL35A, in about 30% of patients. However, the genetic basis of the remaining 70% of cases is still unknown. Here, we report the second known mutation in RPS17 and probable pathogenic mutations in three more RP genes, RPL5, RPL11, and RPS7. In addition, we identified rare variants of unknown significance in three other genes, RPL36, RPS15, and RPS27A. Remarkably, careful review of the clinical data showed that mutations in RPL5 are associated with multiple physical abnormalities, including craniofacial, thumb, and heart anomalies, whereas isolated thumb malformations are predominantly present in patients carrying mutations in RPL11. We also demonstrate that mutations of RPL5, RPL11 ,o rRPS7 in DBA cells is associated with diverse defects in the maturation of ribosomal RNAs in the large or the small ribosomal subunit production pathway, expanding the repertoire of ribosomal RNA processing defects associated with DBA. Diamond-Blackfan anemia (DBA) (MIM 105650) is an inherited congenital bone-marrow-failure syndrome, characterized by normochromic macrocytic anemia and absence or insufficiency of erythroid precursors in otherwise normocellular bone marrow. 1 Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary-system defects, that are present in ~30%–50% of patients, reflecting the fact that DBA is a broad disorder of development. 2–4 Laboratory findings such as increased mean corpuscular volume (MCV), elevated erythrocyte adenosine deaminase activity (eADA), and hemoglobin F are observed in a majority of, but not in all, DBA patients. 5,6 The disease is clinically heterogenous, and within affected families, some individuals can exhibit mild or absent anemia, with only subtle indications of erythroid abnormalities, such as macrocytosis or elevated eADA and/or HbF. Additionally, increased risk of malignancy—in particular, AML and solid tumors, including osteogenic sarcoma 7,8 —has