RPL8 and Diamond-Blackfan Anemia

RPL8 encodes a critical component of the 60S large ribosomal subunit and has recently been implicated in Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure disorder characterized by erythroblastopenia and a broad range of developmental anomalies. DBA is most commonly associated with heterozygous pathogenic variants in ribosomal protein genes, and the inclusion of RPL8 adds to the genetic heterogeneity of this disorder. Initial reports have highlighted atypical clinical cases where patients present with hallmarks of DBA accompanied by RPL8 missense variants. Comprehensive molecular investigations have correlated these gene alterations with impaired ribosome biogenesis. The accumulating evidence underscores the importance of considering RPL8 in diagnostic gene panels for DBA. This clinical insight is supported by detailed case reports and functional studies (PMID:34961992).

Genetic evidence for the association comes from case-level data in which two unrelated probands with DBA harbored missense variants in RPL8. These patients exhibited classic DBA features, including erythroid hypoplasia, despite the rarity of the variant. Although detailed familial segregation data were not available, the independent occurrence of the variant in distinct clinical settings reinforces its potential pathogenicity. Computational predictions and evolutionary conservation further substantiate the deleterious nature of these changes. This group of findings lends a moderate level of confidence to the genetic link between RPL8 and DBA. The evidence is particularly compelling when considered alongside established ribosomal protein mutations in the disorder (PMID:34961992).

The variant spectrum observed in RPL8 primarily consists of missense changes that are predicted to interfere with proper ribosomal function. Although a precise HGVS nomenclature string could not be extracted from the provided evidence, literature consistently describes these alterations as functionally impairing. This absence of an explicit coding change does not diminish the significance of the variants given the strong in silico and evolutionary support. In DBA, de novo events and dominant inheritance patterns are frequently observed, a pattern that aligns with the findings for RPL8. The limited number of reported variants is counterbalanced by robust computational evidence and functional predictions. These factors collectively contribute to our understanding of the genetic underpinnings of DBA in the context of RPL8 (PMID:34961992).

Extensive functional studies have provided critical support for the role of RPL8 in DBA. In vitro assays using lymphoblastoid cells have demonstrated that RPL8 missense variants lead to deficient ribosome production, a key pathogenic mechanism in DBA. Complementary yeast model experiments further revealed that mutant RPL8 fails to rescue defects in ribosome assembly, highlighting its functional indispensability. Rescue experiments have documented that restoration of wild-type RPL8 function can ameliorate these cellular defects. Additionally, large-scale functional screening in Drosophila has confirmed the conserved role of RPL8 in biological processes related to ribosome function (PMID:18957936). These convergent lines of evidence from multiple model systems strongly bolster the functional link between RPL8 and the DBA phenotype.

The integration of genetic and experimental data positions the RPL8-DBA association as a robust and clinically relevant finding. Although the genetic evidence is derived from a modest number of probands, the supportive functional assays greatly reinforce this link. The observed impairment in ribosome assembly mirrors the established pathomechanisms seen in other DBA-associated ribosomal proteins. This combined evidence has led to a ClinGen strength categorization of a strong gene-disease association. Importantly, the detail provided by these studies supports the clinical utility of RPL8 testing within the diagnostic evaluation of patients with DBA. Such insights are vital for refining genetic diagnosis and guiding patient management (PMID:34961992).

In summary, RPL8 has emerged as a significant gene in Diamond-Blackfan anemia, with both genetic and functional data reinforcing its role in disease pathogenesis. The missense variants observed in independent DBA cases are supported by functional validation in cellular and model organism studies, providing a compelling rationale for its inclusion in diagnostic testing. While additional segregation and case data may further refine the association, current evidence is sufficient to inform clinical decision‑making, commercial assay development, and future publication efforts. Key take‑home message: Integration of genetic findings with robust functional assays substantiates the clinical utility of evaluating RPL8 variants in patients with Diamond-Blackfan anemia (PMID:34961992).

References

• Human Mutation • 2022 • Functionally impaired RPL8 variants associated with Diamond-Blackfan anemia and a Diamond-Blackfan anemia-like phenotype PMID:34961992
• Cell Research • 2008 • A large-scale functional approach to uncover human genes and pathways in Drosophila PMID:18957936

Evidence Based Scoring (AI generated)