Diamond-Blackfan Anemia and Bone Marrow Failure via the RPS17 Gene

Diamond-Blackfan anemia (DBA) is a rare, inherited bone marrow failure syndrome characterized by macrocytic anemia, normal leukocyte and platelet numbers, and normocellular bone marrow (Freedman 2000; Gazda and Sieff 2006). Physical anomalies such as craniofacial dysmorphism, thumb and neck anomalies, congenital heart defects, and genitourinary tract defects are found in ~40% of patients and growth retardation is observed in ~30% of patients (Clinton and Gazda 2016). Onset of hematologic complications typically occurs in the first year of life, and the severity of disease varies from mild anemia with no physical anomalies to severe anemia and severe physical anomalies. DBA is also associated with bone marrow failure and increased risk for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

DBA is an autosomal dominant or X-linked disorder caused by inactivating variants within ribosomal protein genes RPS19 (Gazda and Sieff 2006), RPL5 (Gazda et al. 2008), RPL11 (Gazda et al. 2008), RPL35a (Farrar et al. 2008), RPS26 (Doherty et al. 2010), RPS24 (Gazda et al. 2006), RPS17 (Gazda et al. 2008), RPS7 (Gazda et al. 2008), RPS10 (Doherty et al. 2010), RPL26 (Gazda et al. 2012), RPS27 (Wang et al. 2015), RPS29 (Mirabello et al. 2014), RPL31 (Farrar et al. 2014), RPS28 (Gripp et al. 2014), RPL15 (Landowski et al. 2013), RPL27 (Wang et al. 2015), or by variants in the GATA1 (Sankaran et al. 2012) or TSR2 (Gripp et al. 2014) genes. Variants in the RPS19 gene are found in up to 25% of patients (Gazda and Sieff 2006). Variants in the RPL5 (6.6%), PRS26 (6.4%), RPL11 (4.8%), RPL35A (3%), RPS10 (2.6%), RPS24 (2%), and RPS17 (1%) genes are the next most frequent causes of DBA with variants in all other associated genes accounting for a very small fraction of disease (Clinton and Gazda 2016). Approximately 65% of DBA cases are found to have a pathogenic variant in one of the DBA genes (Clinton and Gazda 2016), and 55-60% of DBA cases result from de novo pathogenic variants (Clinton and Gazda 2016) with the remainder of cases resulting from inheritance of a pathogenic variant from an affected parent.

DBA results from loss of protein function and haploinsufficiency. Pathogenic variants consist primarily of missense variants and nonsense or other protein truncating variants including frameshift deletions and insertions. Large, multi-exon or full gene deletions of several ribosomal proteins, in particular RPS19, RPL5, RPL11, RPL35A, RPS26, RPS24, RPS17, and RPL15, have been reported in patients with DBA. Dysfunctional ribosomal proteins are likely to alter the stability and/or function of the ribosomal complex causing destruction of blood-forming cells in the bone marrow and consequent anemia.

Other bone marrow failure syndromes such as Fanconi anemia, severe congenital neutropenia, dyskeratosis congenital, and Shwachman-Diamond syndrome should be considered in addition to DBA during diagnosis.

Approximately 65% of Diamond-Blackfan anemia (DBA) cases are found to have a pathogenic variant in one of the DBA genes (Clinton and Gazda 2016). Variants in the RPS19 gene are found in up to 25% of patients (Gazda and Sieff 2006). Variants in the RPL5 (6.6%), PRS26 (6.4%), RPL11 (4.8%), RPL35A (3%), RPS10 (2.6%), RPS24 (2%), and RPS17 (1%) genes are the next most frequent causes of DBA, with variants in all other associated genes accounting for a very small fraction of disease (Clinton and Gazda 2016).

Our DNA sequencing test involves bidirectional DNA sequencing of all coding exons (exons 1-5) of the RPS17 gene plus ~10 bp of flanking non-coding DNA on either side of each exon. We will also sequence any single exon (Test #100) in family members of patients with a known pathogenic variant or to confirm research results.