Diamond–Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28

Abstract

Patients with physical findings suggestive of Treacher Collins syndrome (TCS) or mandibulofacial dystosis (MFD) and macrocytic anemia diagnostic of Diamond Blackfan anemia (DBA) have been reported. Disease causing genes have been identified for TCS and other MFDs. Mutations in several ribosomal protein genes and the transcription factor GATA1 result in DBA. However, no disease causing mutation had been identified in the reported patients with the combination of TCS/MFD and DBA phenotype, and we hypothesized that pathogenic mutations in a single gene could be identified using whole exome analysis. We studied probands from 6 unrelated families. Combining exome analysis and Sanger sequencing, we identified likely pathogenic mutations in 5/6 families. Two mutations in unrelated families were seen in RPS26, the known DBA10 gene. One variant was predicted to affect mRNA splicing, and the other to lead to protein truncation. In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26. De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene. We conclude that the phenotype combining features of TCS with DBA is genetically heterogeneous. Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth. The phenotype combining TCS/MFD and DBA is highly variable, overlaps with DBA and lies within the phenotypic spectrum of ribosomopathies.

An update on the pathogenesis and diagnosis of Diamond–Blackfan anemia

“…With regard to the “non-RP” genes linked to DBA, TSR2 is known to play a role in ribosome biogenesis, since it is involved in the pre-rRNA processing and binds to RPS26 52 . GATA1 is the major erythroid transcription factor and plays a critical role in regulating normal erythroid differentiation by activating an array of erythroid genes.…”

Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation

“…More recently, disease-causing mutations were also discovered in another X-linked gene, TSR2, which encodes a binding partner of RPS26. 16 …”

Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Cell Transplantation for Inherited Bone Marrow Failure Syndromes: Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation

“…Those in the 60s large ribosomal subunit include RPL11, RPL5, RPL35A, RPL26, RPL15, RPL31 , and RPL27 (Figure 3). Rare patients with clinical DBA had mutations in X-linked GATA1 and TSR2 [79,80]. DBA is also a cancer-predisposition syndrome [81].…”