RPL35A – Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia characterized by macrocytic anemia, reticulocytopenia, and in ~40–50% of patients, congenital anomalies (MONDO:0015253). Heterozygous loss-of-function variants in RPL35A cause DBA via haploinsufficiency.

Genetic evidence supports an autosomal dominant inheritance: a multi-institutional study of 45 individuals with pathogenic RPL35A germline variants and 21 additional unrelated cases establish RPL35A as a causative DBA gene (PMID:32241839). Moreover, six patients with 3q27.2–qter deletions encompassing RPL35A presented with DBA features (PMID:28432740), confirming dosage sensitivity.

The spectrum of pathogenic alleles includes single-nucleotide frameshift and splice-site mutations as well as large gene deletions. A representative variant is c.118_119del (p.Glu40fs), identified in a Russian DBA cohort (PMID:25946618).

Functional studies in zebrafish demonstrate that morpholino-mediated knockdown of rpl35a leads to a striking reduction of erythroid cells and developmental defects in head and tail, mirroring DBA erythropoietic failure (PMID:18653748).

Genotype-phenotype correlations reveal that large RPL35A deletions are significantly associated with steroid-resistant anemia, neutropenia, craniofacial and gastrointestinal abnormalities (p<0.01) compared to patients with other variant classes (PMID:32241839).

One patient with a 3q27.2–qter deletion presented immunodeficiency in addition to DBA, but normal RNF168 function excluded RIDDLE syndrome, suggesting immunodeficiency may arise from secondary effects or unrecognized gene interactions (PMID:28432740).

Collectively, these data achieve a definitive clinical validity classification and support robust diagnostic testing for RPL35A in suspected DBA cases. Key take-home: RPL35A haploinsufficiency underlies an autosomal dominant ribosomopathy with characteristic erythroid failure and multisystem involvement, guiding genetic diagnosis and management.

References

• Haematologica • 2021 • Genotype-phenotype association and variant characterization in Diamond-Blackfan anemia caused by pathogenic variants in RPL35A. PMID:32241839
• American journal of medical genetics. Part A • 2017 • Novel 3q27.2-qter deletion in a patient with Diamond-Blackfan anemia and immunodeficiency: Case report and review of literature. PMID:28432740
• Human molecular genetics • 2008 • Deficiency of ribosomal protein S19 during early embryogenesis leads to reduction of erythrocytes in a zebrafish model of Diamond-Blackfan anemia. PMID:18653748
• Pediatric blood & cancer • 2015 • Clinical and genomic heterogeneity of Diamond Blackfan anemia in the Russian Federation. PMID:25946618

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