ORPHA: 124; DO: 0111888;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.2 | Diamond-Blackfan anemia 10 | 613309 | Autosomal dominant | 3 | RPS26 | 603701 |
A number sign (#) is used with this entry because Diamond-Blackfan anemia-10 (DBA10) is caused by heterozygous mutation in the gene encoding ribosomal protein S26 (RPS26; 603701) on chromosome 12q13.
Diamond-Blackfan anemia (DBA) is an inherited red blood cell aplasia that usually presents in the first year of life. The main features are normochromic macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow. Patients show growth retardation, and approximately 30 to 50% have craniofacial, upper limb, heart, and urinary system congenital malformations. The majority of patients have increased mean corpuscular volume, elevated erythrocyte adenosine deaminase activity, and persistence of hemoglobin F. However, some DBA patients do not exhibit these findings, and even in the same family, symptoms can vary between affected family members (summary by Landowski et al., 2013).
For a discussion of genetic heterogeneity of Diamond-Blackfan anemia, see DBA1 (105650).
McFarren et al. (2007) reported a female infant with DBA associated with craniofacial anomalies. She had intrauterine growth retardation and was delivered via cesarean section at 37 weeks' gestation due to heart rate decelerations. At birth, she was noted to have jaundice, atresia of the external auditory canals, and cleft soft palate. She had persistent failure to thrive associated with steroid-resistant reticulocytopenic macrocytic anemia requiring transfusion. Bone marrow biopsy showed decreased erythrocyte precursors. Additional features included anomalous right middle ear ossicles, vestibule, and semicircular canals; left cross-fused renal ectopia; ventricular septal defect; and diaphragmatic hernia. McFarren et al. (2007) noted the phenotypic similarities to Treacher Collins syndrome (TCS; 154500). Genetic analysis excluded mutations in the DBA-associated genes RPS19 (603474) and RPS24 (602412).
Gripp et al. (2014) restudied as 'patient 3' the patient of McFarren et al. (2007) and noted microtia, hearing loss, midface hypoplasia, a wide neck, and overall poor growth, but normal cognitive development at 8 years of age.
Handler et al. (2009) reported a girl with DBA associated with mandibulofacial dysostosis. At birth, she was noted to have micrognathia, cleft palate, low-set and posteriorly rotated ears, and mandibulofacial dysostosis with choanal atresia resulting in respiratory insufficiency. Additional features included ventricular septal defect and patent ductus arteriosus. She underwent successful mandibular surgery. The patient's father and sister both had macrocytic anemia consistent with DBA, but no mandibulofacial abnormalities.
Gripp et al. (2014) noted that the patient reported by Handler et al. (2009) ('patient 2' of Gripp et al. (2014)) had hearing loss, multiple red cell infusions, and poor growth, but that development was normal at age 5 years. The patient's sister had a duplicated right kidney.
The transmission pattern of DBA10 in the family reported by Handler et al. (2009) was consistent with autosomal dominant inheritance.
Doherty et al. (2010) sequenced 35 ribosomal protein genes in a cohort of 117 patients with Diamond-Blackfan anemia who were negative for mutation in 7 known DBA genes and identified 9 mutations in the RPS26 gene in 12 probands (see, e.g., 603701.0001-603701.0005). None of the mutations were found in at least 520 chromosomes from a control population of similar, largely European origin. Doherty et al. (2010) noted that 1 of the mutation-positive patients (see 603701.0002) had cleft lip and palate, making RPS26 the third gene causing DBA, the other 2 being RPL5 (603634) and RPL11 (604175), in which mutation is associated with clefting. The authors estimated that RPS26 mutations are present in about 6.4% of the overall DBA population.
Landowski et al. (2013) performed array CGH for copy number variation in 87 probands with Diamond-Blackfan anemia who were negative for mutation in 10 known DBA-associated ribosomal protein genes and identified a large deletion encompassing all 4 exons of the RPS26 gene (603701.0006) in a transfusion-dependent female patient.
In the patient with DBA and mandibulofacial dysostosis reported by McFarren et al. (2007), Gripp et al. (2014) identified a de novo heterozygous splice site mutation in the RPS26 gene (603701.0008).
In 3 members of a family with DBA10 originally reported by Handler et al. (2009), Gripp et al. (2014) identified a heterozygous truncating mutation in the RPS26 gene (R87X; 603701.0007). The mutation, which was found by sequencing of candidate ribosomal protein genes, segregated with the disorder in the family. Functional studies of the variant were not performed.
Doherty, L., Sheen, M. R., Vlachos, A., Choesmel, V., O'Donohue, M.-F., Clinton, C., Schneider, H. E., Sieff, C. A., Newburger, P. E., Ball, S. E., Niewiadomska, E., Matysiak, M., Glader, B., Arceci, R. J., Farrar, J. E., Atsidaftos, E., Lipton, J. M., Gleizes, P.-E., Gazda, H. T. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Am. J. Hum. Genet. 86: 222-228, 2010. Note: Erratum: Am. J. Hum. Genet 86: 655-656, 2010. [PubMed: 20116044] [Full Text: https://doi.org/10.1016/j.ajhg.2009.12.015]
Gripp, K. W., Curry, C., Olney, A. H., Sandoval, C., Fisher, J., Chong, J. X.-L., UW Center for Mendelian Genomics, Pilchman, L., Sahraoui, R., Stabley, D. L., Sol-Church, K. Diamond-Blackfan anemia with mandibulofacial dystostosis (sic) is heterogeneous, including the novel DBA genes TSR2 and RPS28. Am. J. Med. Genet. 164A: 2240-2249, 2014. [PubMed: 24942156] [Full Text: https://doi.org/10.1002/ajmg.a.36633]
Handler, M. Z., Alabi, O., Miller, J. Curvilinear mandibular distraction in a patient with mandibulofacial dysostosis associated with Diamond-Blackfan anemia. J. Craniofac. Surg. 20: 1417-1419, 2009. [PubMed: 19816270] [Full Text: https://doi.org/10.1097/SCS.0b013e3181aee34e]
Landowski, M., O'Donohue, M.-F., Buros, C., Ghazvinian, R., Montel-Lehry, N., Vlachos, A., Sieff, C. A., Newburger, P. E., Niewiadomska, E., Matysiak, M., Glader, B., Atsidaftos, E., Lipton, J. M., Beggs, A. H., Gleizes, P.-E., Gazda, H. T. Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia. Hum. Genet. 132: 1265-1274, 2013. [PubMed: 23812780] [Full Text: https://doi.org/10.1007/s00439-013-1326-z]
McFarren, A., Jayabose, S., Ozkaynak, M. F., Tugal, O., Sandoval, C. Cleft palate, bilateral external auditory canal atresia, and other midline defects associated with Diamond-Blackfan anemia: case report. J. Pediat. Hemat. Oncol. 29: 338-340, 2007. [PubMed: 17483715] [Full Text: https://doi.org/10.1097/MPH.0b013e31805d8f45]