ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000010.10) (NC_000010.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
23812780 Landowski et al. 2013 studied 87 unrelated patients with a clinical diagnosis of Diamond Blackfan Anemia (DBA) (thought to be a disorder of ribosome biogenesis and/or function); all patients had previously had negative sequencing studies of all currently known ribosomal protein (RP) genes. The authors screened the patients using an array with enriched coverage over known RP genes and 117 additional genes "shown to be involved in human ribosomal biogenesis or homologous to yeast pre-ribosomal factors." They identified 6 deletions in RP genes amongst 6 patients, including a de novo 1.7kb deletion in RPS24 including exons 1, 2, and part of 3. The authors showed that pre-ribosomal RNA processing was affected in cell lines established from patient cells.
17186470 Gazda et al. 2006: The authors describe a cohort of 185 unrelated probands (representing both familial and sporadic cases) with clinical diagnoses of DBA and no known pathogenic mutations in the RPS19 gene. Following linkage studies in an extensive family with 10 informative meioses, the authors identified a heterozygous nonsense variant in exon 4 of RPS24 cosegregating with disease. The authors then sequenced RPS24 in the rest of the cohort, identifying another nonsense variant in exon 2 and a splice site variant resulting in skipping of exon 2 in two unrelated probands. These three variants were not found when the authors sequenced RPS24 in 210 ethnically matched controls. The authors report that "qrt-PCR showed a reduced level of total RPS24 mRNA from lymphoblastoid cell lines in both probands...with nonsense mutations... and premature stop codons, suggesting degradation of mutated transcript due to nonsense-mediated decay." Additional functional studies on RPS24 suggesting it causes DBA through loss-of-function mechanisms are reported by this group in PMID: 18230666. PMID: 29044489 Arbiv et al. 2018: The authors studied a cohort of 74 patients diagnosed with DBA. A frameshift variant (c.66_67delAA) of RPS24 was found in one patient. PMID: 25946618 Smetanina et al. 2015: A sporadic mutation in the RPS24 gene was identified in one DBA case. It was a donor splicing site mutation at intron 1 (c.3+1G>T). PMID: 19689926 Badhai et al. 2009: Primary fibroblasts from DBA patients with a truncating mutation (c.1A>G, p.M1?) in RPS24 have a marked reduction in proliferative capacity. Authors suggest that their functional evidence demonstrates that the RPS24 variant results in haploinsufficiency. PMID: 26136524 Ghemlas et al. 2015: Among 75 inherited bone marrow failure syndromes (IBMFSs) patients with clinically classified IBMFSs, they identified a nucleotide-level causal mutation (c.4-2A>G splicing variant) in one DBA patient. The same variant (c.1A>G, p.Met1?) with Badhai et al 2009, which causing start codon lost was also found in another patient. PMID: 20960466 Boria et al. 2010: The authors reported a mutation update for DBA that includes a sporadic donor splice donor variant (c.390+1G>A, p.0?) of RPS24.
  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity