Genotype-phenotype association and variant characterization in Diamond-Blackfan anemia caused by pathogenic variants in <i>RPL35A</i>

Abstract

Diamond Blackfan anemia (DBA) is predominantly an autosomal dominant inherited red cell aplasia primarily caused by pathogenic germline variants in ribosomal protein genes. DBA due to pathogenic RPL35A variants has been associated with large 3q29 deletions and phenotypes not common in DBA. We conducted a multi-institutional genotype-phenotype study of 45 patients with DBA associated with pathogenic RPL35A germline variants and curated the variant data on 21 additional cases from the literature. Genotype-phenotype analyses were conducted comparing patients with large deletions versus all other pathogenic variants in RPL35A. Twenty-two of the 45 cases had large deletions in RPL35A. After adjusting for multiple tests, a statistically significant association was observed between patients with a large deletion and steroid-resistant anemia, neutropenia, craniofacial abnormalities, chronic gastrointestinal problems, and intellectual disabilities (p&lt;0.01) compared with all other pathogenic variants. Non-large deletion pathogenic variants were spread across RPL35A with no apparent hot spot and 56% of the individual family variants were observed more than once. In this, the largest known study of DBA patients with pathogenic RPL35A variants, we determined that patients with large deletions have a more severe phenotype that is clinically different from those with non-large deletion variants. Genes of interest also deleted in the 3q29 region that could be associated with some of these phenotypic features include LMLN and IQCG. Management of DBA due to large RPL35A deletions may be challenging due to complex problems and require comprehensive assessments by multiple specialists including immunologic, gastrointestinal, and developmental evaluations to provide optimal multidisciplinary care.

Diamond-Blackfan anemia

“…Phenotypic/geno typic cor re la tion is not read ily evi dent, although it is well established that patients with DBA car ry ing a RPS19 gene muta tion exhibit less malformation com pared with oth ers but appear to exhibit a more severe hema to logic phe no type and are fre quently man aged by a trans fu sion pro gram. 33 Neutropenia is more fre quently asso ci ated with RPL35a, 34 car diac anom a lies with RPS24, 35 cleft pal ate with RPL5, and thumbs anom a lies with RPL11 36 gene muta tions. Other RP genes have been found to be mutated in small sub sets of DBAaffected patients, each affect ing <1% of DBA cohorts (Figure 2).…”

Late‐onset familial Diamond–Blackfan anemia with neutropenia caused by RPL35A variant

“…The phenotypes and family history of our patient were suggestive of DBA, and some RPL35A variants are known to be pathogenic for DBA. The p.Leu28del in‐frame variant, which was detected in our cases, was estimated to be the most common RPL35A variant 4 . Some familial cases with RPL35A variants were described in a Japanese cohort but accurate data on their frequency and clinical characteristics are limited 5 …”

RPL19 Is a Prognostic Biomarker and Promotes Tumor Progression in Hepatocellular Carcinoma

“…RPL27A was also identified as a biomarker for squamous cervical cancer ( Fjeldbo et al, 2016 ). The RPL35A gene is located at chromosome 3q29-qter ( Colombo et al, 1996 ), and almost all studies have suggested that Diamond-Blackfan anemia is caused by deletion of the RPL35A gene ( Farrar et al, 2008 , 2011 ; Gianferante et al, 2020 ). Finally, the RPS12 gene has been shown to be related to the biological functions of various plants ( Lee et al, 2019 ) and insects ( Ji et al, 2019 ; Kirby and Koslowsky, 2020 ).…”