Expansion of germline RPS20 mutation phenotype to include Diamond–Blackfan anemia

Abstract

Diamond-Blackfan anemia (DBA) is a ribosomopathy of variable expressivity and penetrance characterized by red cell aplasia, congenital anomalies, and predisposition to certain cancers, including early-onset colorectal cancer (CRC). DBA is primarily caused by a dominant mutation of a ribosomal protein (RP) gene, although approximately 20% of patients remain genetically uncharacterized despite exome sequencing and copy number analysis. Although somatic loss-of-function mutations in RP genes have been reported in sporadic cancers, with the exceptions of 5q-myelodysplastic syndrome (RPS14) and microsatellite unstable CRC (RPL22), these cancers are not enriched in DBA. Conversely, pathogenic variants in RPS20 were previously implicated in familial CRC; however, none of the reported individuals had classical DBA features. We describe two unrelated children with DBA lacking variants in known DBA genes who were found by exome sequencing to have de novo novel missense variants in RPS20. The variants affect the same amino acid but result in different substitutions and reduce the RPS20 protein level. Yeast models with mutation of the cognate residue resulted in defects in growth, ribosome biogenesis, and polysome formation. These findings expand the phenotypic spectrum of RPS20 mutation beyond familial CRC to include DBA, which itself is associated with increased risk of CRC.

From APC to the genetics of hereditary and familial colon cancer syndromes

“…In a similar fashion to the discovery of PPAP, a combination of linkage analysis and WES identified a truncating variant of RPS20 in association with MMR-proficient CRC in a four-generation family ( 88 , 95 ). Subsequent studies have since identified three RPS20 mutations in familial CRC cases ( 96 , 97 ) and two in Diamond-Blackfan anemia (DBA) patients ( 98 ). Available experience suggests that only a small fraction of FCCTX susceptibility genes have been discovered so far, and that private genes and mutations are common, strengthening the idea of the heterogeneous genetic background of FCCTX ( 94 , 99 ).…”

Pathogenic germline IKZF1 variant alters hematopoietic gene expression profiles

“…They later had autoimmune GI manifestations that are not typical of DBA but have been reported. Notably, chronic colitis of unclear etiology has recently been described in two individuals with DBA found to have germline pathogenic variants in RPS20 ( Bhar et al 2020 ).…”

“…The majority of patients with DBA have autosomal dominant pathogenic germline variants in genes encoding ribosomal biogenesis proteins (small and large subunit components), with two X-linked recessive genes (GATA1 and TSR2) also causative of DBA (Bhar, et al 2020, Boria, et al 2010, Campagnoli , et al 2008, Draptchinskaia, et al 1999, Farrar, et al 2011, Gazda, et al 2012, Gripp, et al 2014, Landowski, et al 2013, Mirabello, et al 2014, Narla and Ebert 2010, Sankaran, et al 2012, Wang, et al 2015.…”

“…Phenotypic heterogeneity is often observed, even within affected members of the same family ( Campagnoli et al 2004 ; Farrar and Dahl 2011 ; Alter et al 2018 ; Vlachos et al 2018 ). The majority of patients with DBA have autosomal dominant pathogenic germline variants in genes encoding ribosomal biogenesis proteins (small and large subunit components), with two X-linked recessive genes ( GATA1 and TSR2 ) also causative of DBA ( Draptchinskaia et al 1999 ; Campagnoli et al 2008 ; Boria et al 2010 ; Narla and Ebert 2010 ; Farrar et al 2011 ; Gazda et al 2012 ; Sankaran et al 2012 ; Landowski et al 2013 ; Gripp et al 2014 ; Mirabello et al 2014 ; Wang et al 2015 ; Bhar et al 2020 ).…”

Functionally impaired RPL8 variants associated with Diamond–Blackfan anemia and a Diamond–Blackfan anemia‐like phenotype

“…In addition, the gene discovery rate has expanded exponentially (Ulirsch et al, 2018). To date, over 20 genes have been associated with DBA, with all but two of them encoding proteins of the small or large ribosomal subunits (RPSs, RPLs, respectively): RPS19, RPL5, RPL11, RPS26, RPL35A, RPS10, RPS17, RPS24, RPS7, RPS15A, RPS20, RPS27, RPS28, RPS29, RPL9, RPL15, RPL18, RPL26, RPL27, RPL31, RPL35 (Aubert et al, 2018;Bhar et al, 2020;Doherty et al, 2010;Draptchinskaia et al, 1999;Farrar et al, 2008Farrar et al, , 2014Gazda et al, 2006Gazda et al, , 2008Ikeda et al, 2017;Landowski et al, 2013;Lezzerini et al, 2020;Mirabello et al, 2014Mirabello et al, , 2017Sankaran et al, 2012;Wang et al, 2015). The first eight genes together comprise roughly 50% of DBA cases.…”