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This summary reviews the clinical and experimental evidence linking variants in RPS7 with Diamond-Blackfan Anemia (DBA). Several independent case reports (PMID:32772263) have identified heterozygous RPS7 variants in affected individuals, with one report describing a novel splice site mutation leading to a cryptic splicing event and a truncated protein product. In one family, both an affected mother and her daughter were shown to carry the splice variant, with the daughter presenting with occipital meningocele and the mother experiencing spontaneous remission later in life. This segregation of variants with clinical manifestations supports a clear genotype-phenotype correlation.
Multiple mutation types in RPS7 have been reported including splice site, missense and 5'-UTR variants. In one study, a missense variant, reported as c.400G>T (p.Val134Phe), was identified in a female patient and her asymptomatic family members (PMID:35871033). The diversity in the variant spectrum underlines the role of RPS7 in protein dosage and function, and the recurrence of different types of mutations emphasizes its contribution to DBA pathology. Additional case studies have detected RPS7 variants in cohorts of DBA patients, further reinforcing its genetic involvement.
Segregation data from these reports indicates that affected individuals in multiple families share a common variant that is absent in unaffected relatives. For instance, the segregation observed in the splice site mutation case demonstrates that the variant co-segregated with both hematological and non-hematological manifestations, including craniofacial anomalies. This type of familial clustering and co-segregation is a key factor in evaluating the genetic contribution of RPS7 to Diamond-Blackfan Anemia.
Functional studies provide experimental confirmation of the pathogenicity of RPS7 mutations. In vitro mini-gene assays have demonstrated that the c.508-3T>G splice site variant leads to aberrant splicing and formation of a transcript with a 64 bp deletion, resulting in a frameshift (p.Val170SerfsTer8) (PMID:32772263). Moreover, cellular assays of the missense mutation c.400G>T (p.Val134Phe) have shown altered protein translational activity and induction of ribosomal stress (PMID:35871033). These experimental findings align closely with the clinical phenotype of DBA, supporting a direct mechanistic link between the molecular defect and disease manifestation.
The integration of multiple lines of evidence—including genetic findings from case reports, segregation analyses, and robust functional studies—underscores that RPS7 has a significant and reproducible role in the pathogenesis of Diamond-Blackfan Anemia. While additional cases and further functional studies may continue to extend the total evidence beyond the current scoring maximum, the present data already provide a strong basis for using RPS7 in diagnostic decision‑making and potential commercial screening applications.
Key takeaway: RPS7 is a causative gene for Diamond-Blackfan Anemia, with both genetic and experimental studies confirming that its variants lead to a deleterious impact on ribosomal function and hematological development, thereby serving as a critical marker for clinical diagnostics.
Gene–Disease AssociationStrongMultiple independent reports have identified deleterious RPS7 variants in DBA with consistent segregation patterns across families (PMID:32772263, PMID:35871033). Genetic EvidenceStrongDiverse pathogenic variants in RPS7, including splice site and missense mutations, have been reported in unrelated probands and show clear segregation with the DBA phenotype. Functional EvidenceModerateFunctional analyses using mini-gene constructs and cellular assays confirm that RPS7 mutations disrupt normal splicing, translational activity, and induce ribosomal stress, which are concordant with the clinical presentations of DBA. |