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The association between RPL15 and Diamond‑Blackfan anemia (DBA) (Diamond-Blackfan anemia) currently meets Moderate clinical validity according to ClinGen‑style criteria. Evidence derives from at least 7 unrelated probands with rare heterozygous coding or copy‑number variants in RPL15 that are plausibly or demonstrably loss‑of‑function and segregate with a DBA phenotype in small nuclear families or trios
(PMID:23812780, PMID:29599205). Functional studies in patient‑derived cells show concordant pre‑rRNA processing defects, impaired 60S ribosomal subunit production, proliferation arrest, and p53 pathway activation, consistent with the known ribosomopathy mechanism of DBA
(PMID:29599205). Longitudinal clinical observation documents a characteristic red‑cell aplasia phenotype with a distinctive predisposition to severe hydrops fetalis and spontaneous remission among truncating‑variant carriers
(PMID:29599205). However, the total number of independently ascertained families remains small and segregation data are limited, so a Definitive classification is not yet justified.
Inheritance pattern and severity. All reported individuals with RPL15‑related DBA carry heterozygous RPL15 variants without evidence for biallelic involvement, consistent with an autosomal dominant, incompletely penetrant model. The disease presents as a severe congenital or perinatal red‑cell aplasia, frequently requiring transfusion support in infancy, and in truncating‑variant carriers may manifest as hydrops fetalis requiring intrauterine transfusions
(PMID:29599205). Overall clinical severity is high at presentation but can be followed by spontaneous remission in a subset.
Case reports and series. An array‑CGH study of DBA identified one proband with a novel large deletion encompassing RPL15, among a cohort screened for ribosomal protein gene deletions
(PMID:23812780). A subsequent European DBA consortium cohort described six unrelated probands with RPL15 variants: four with truncating variants (three with the recurrent c.242dup (p.Tyr81Ter), one with c.85C>T (p.Gln29Ter)) and two with missense variants (c.29T>C (p.Leu10Pro), c.458A>C (p.Lys153Thr))
(PMID:29599205). In the same study, an additional truncating variant c.211C>T (p.Arg71Ter) and a missense variant c.553G>A (p.Gly185Ser) are listed, supporting a small but growing allelic series.
Segregation and family data. The available publications emphasize sporadic cases and trio analyses; detailed segregation counts are not fully provided. The 2018 consortium report notes three unrelated carriers of the recurrent c.242dup (p.Tyr81Ter) allele with similar clinical courses, supporting pathogenicity through allelic recurrence rather than extensive pedigree segregation
(PMID:29599205). The 2013 deletion case is likewise reported as a single affected individual, but the de novo or inherited status is not fully detailed
(PMID:23812780). Based on the supplied evidence, additional affected relatives are either not reported or not quantifiable.
Variant spectrum. The current RPL15 DBA spectrum includes:
Phenotypic and population considerations. Across reported cases, patients present with classic DBA hallmarks: normochromic macrocytic anemia, reticulocytopenia, and marked reduction of erythroid progenitors, with frequent growth delay and congenital anomalies in the broader cohort background
(PMID:23812780, PMID:29599205). A distinctive feature of RPL15‑mutated DBA is the high rate of hydrops fetalis (75% of truncating‑variant carriers) and early treatment independence in all three probands with c.242dup (p.Tyr81Ter), who became transfusion‑independent by 4–16 months of age and maintained normal blood counts on follow‑up
(PMID:29599205). Reported individuals were ascertained through European DBA consortium cohorts; specific ethnic founder effects beyond the recurrent c.242dup allele are not yet established.
Mechanistic framework. RPL15 encodes a component of the 60S large ribosomal subunit. Like RPL26, it is required both for 60S subunit assembly and efficient cleavage of internal transcribed spacer 1 (ITS1) during pre‑rRNA processing
(PMID:23812780). The disease mechanism is most consistent with haploinsufficiency leading to ribosomal stress and p53 activation, in line with other ribosomal protein–associated forms of DBA.
Patient‑derived cell studies. In the European DBA consortium study, primary cells from RPL15‑mutated patients displayed pre‑rRNA processing defects, specifically impaired ITS1 cleavage, and a marked reduction in mature 60S ribosomal subunits
(PMID:29599205). These abnormalities parallel those seen in other DBA‑causing ribosomal protein defects and provide direct mechanistic linkage between RPL15 disruption and ribosome biogenesis failure.
Erythroid‑specific assays. Red‑cell culture assays using primary erythroblasts from RPL15‑mutant patients revealed severely reduced proliferation, delayed erythroid differentiation, increased TP53 activity, and heightened apoptosis
(PMID:29599205). These findings recapitulate key pathophysiologic features of DBA—ineffective erythropoiesis and p53‑mediated progenitor loss—and establish that RPL15 deficiency directly compromises human erythroid development.
Functional impact of deletions. In the array‑CGH study, cell lines derived from patients carrying large RPL15‑inclusive deletions likewise showed altered pre‑rRNA processing, reinforcing that both structural and coding variants converge on the same loss‑of‑function pathway
(PMID:23812780). Combined, these experiments provide coherent mechanistic evidence in human hematopoietic cells without reliance on overexpression or artificial model systems.
No publications in the supplied evidence explicitly dispute the RPL15–DBA association or reassign RPL15 variants to alternative primary phenotypes. Limitations include the small number of families, limited formal segregation data, and absence of long‑term malignancy or extra‑hematologic outcome data specific to RPL15 carriers. Additionally, spontaneous remission in multiple truncating‑variant carriers suggests variable expressivity and incomplete penetrance, which should be considered in counseling and in variant interpretation.
The convergence of: (1) rare heterozygous truncating and missense RPL15 variants and a large deletion in multiple independent DBA probands; (2) a characteristic clinical pattern featuring fetal hydrops, severe early anemia, and frequent spontaneous remission; and (3) robust functional evidence for impaired 60S biogenesis, defective pre‑rRNA processing, and p53‑mediated erythroid failure, collectively supports a Moderate gene–disease association between RPL15 and autosomal dominant Diamond‑Blackfan anemia. Additional independent families and segregation data would likely elevate this relationship toward a Strong/Definitive classification. At present, inclusion of RPL15 on diagnostic gene panels for congenital red‑cell aplasia and ribosomopathies is clinically justified, and truncating or clearly disruptive variants should be considered strong candidates for pathogenicity in the appropriate phenotype.
Key take‑home sentence: Heterozygous loss‑of‑function and functionally disruptive missense variants in RPL15 cause a distinct autosomal dominant form of Diamond‑Blackfan anemia characterized by fetal hydrops and potential spontaneous remission, supported by convergent genetic and mechanistic evidence.
Gene–Disease AssociationModerateAt least 7 unrelated probands with heterozygous truncating, missense, or deletion variants in RPL15 and Diamond-Blackfan anemia, including a recurrent truncating allele and one large deletion, plus strong functional concordance in patient-derived cells; family numbers remain limited and segregation data are sparse. Genetic EvidenceModerateOne proband with a large RPL15 deletion and at least six unrelated probands with heterozygous truncating or missense variants showing a consistent DBA phenotype and a recurrent c.242dup (p.Tyr81Ter) allele; however, detailed segregation and population-based effect estimates are not yet available. Functional EvidenceStrongPatient-derived cells with RPL15 variants show defective pre-rRNA processing, reduced 60S ribosomal subunit formation, proliferation arrest, delayed erythroid differentiation, increased TP53 activity, and apoptosis, all consistent with the established ribosomopathy/p53 mechanism of DBA and replicated across both deletion and point-mutation cases. |