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The association between RPS28 and Diamond-Blackfan anemia is supported by evidence from both single‐patient case reports and multi‑patient studies. In a recent case report, a heterozygous mutation in RPS28 was detected in a young patient with features of Diamond-Blackfan anemia and a Pierre‑Robin sequence, including cleft palate, micrognathia, low‑set ears, downslanted palpebral fissures, airway obstruction, short neck, and hypertelorism (PMID:40135709). This report highlighted the novelty of the pathogenic variant and its potential role in disrupting ribosome function, a hallmark of ribosomopathies.
Based on multiple independent studies, the clinical validity of the RPS28–Diamond-Blackfan anemia relationship is rated as Strong. In one multi‑patient study, de novo mutations affecting the start codon of RPS28 were identified in two unrelated probands (PMID:24942156), reinforcing the genetic basis of the association through recurrent variant discovery and supportive genetic evidence from whole‑exome sequencing analyses.
Genetic evidence further supports autosomal dominant inheritance for Diamond-Blackfan anemia, as the causative variants occur in a heterozygous state. The de novo mutation reported, for example, “c.1A>G (p.Met1Val)” was identified by both multi‑family studies and functional assessments. Although familial segregation data are limited in this context (0 additional affected relatives), the recurrence of this mutation in independent cohorts provides compelling support (PMID:24942156).
Functional investigations have demonstrated that the RPS28 mutation disrupts normal ribosome biogenesis and protein synthesis, leading to impaired erythropoiesis—a central feature of Diamond‑Blackfan anemia. Patient‑derived cellular models and complementary in vivo studies have recapitulated the hematologic and developmental anomalies observed clinically, providing moderate functional evidence to bolster the genetic findings (PMID:24942156).
The convergence of genetic and experimental data confirms that altered RPS28 function is pathogenic when present as a heterozygous mutation. Further, the functional impact on ribosome assembly correlates well with the distinctive hypocellular bone marrow and congenital anomalies observed in Diamond-Blackfan anemia. Additional evidence from large cohort studies further underscores that mutations in ribosomal protein genes, including RPS28, contribute to the diverse phenotypic spectrum of this disorder (PMID:30503522).
Key take‑home message: The robust genetic and functional evidence supporting RPS28 mutations in Diamond‑Blackfan anemia provides a clear rationale for incorporating genetic testing of RPS28 into diagnostic workflows for affected individuals, thereby enhancing clinical decision‑making and personalized patient care.
Gene–Disease AssociationStrongDe novo RPS28 mutations were identified in at least 2 unrelated probands (PMID:24942156), with functional studies supporting a ribosome biogenesis defect. Genetic EvidenceStrongThe recurrent de novo mutation c.1A>G (p.Met1Val) in RPS28 across independent studies in heterozygous state supports an autosomal dominant mode, despite limited familial segregation data (PMID:24942156). Functional EvidenceModerateFunctional assays in patient‑derived cells and animal models demonstrate disrupted ribosome biogenesis and impaired erythropoiesis, recapitulating the DBA phenotype (PMID:24942156). |