ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000012.11) (NC_000012.12)
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 2.1 kb deletion in RPS26 including exons 1-4 (of 4 exons; Fig 1D). The authors showed that pre-ribosomal RNA processing was affected in cell lines established from patient cells.

Haploinsufficiency phenotype comments:

Shi et al. (2019) presents a case report of a 3 month old neonate with Diamond-Blackfan anemia (DBA) with a de novo frameshift variant (c.96dupG; p.K32fsX5) in RPS26. (PMID: 31277601) Arbiv et al. (2018) using a combination of Sanger sequencing, a clinical NGS DBA gene panel, and arrays (SNP or CGH) identified nucleotide-level variants or large deletions in 10 RP genes in 45 cases out the assessed 74 patients with a clinical diagnosis of Diamond-Blackfan anemia (DBA). Of the RPS26 variants identified two were splicing (c.3+1G>T, c.4-32_21del), one was a frameshift (c.243delC; p.S81RfsX3), and one was a start codon variant (c.1A>G; p.M1V) (Table S2). The inheritance status of these variants is unknown. (PMID: 29044489) Ulirsch et al. (2018) studied a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). Using exon coverage estimates, the authors identified and validated 31 deletions in RP genes. They also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Five cases had either multiple or single exon losses of RPS26 (Table S5); 11 had a frameshift variant, 13 had a splice region variant; 9 with a start loss variant; and 2 with stop gained variants (Table S2). (PMID 30503522) Gripp et al. (2014) using exome and Sanger sequencing studied six unrelated probands presenting with Diamond-Blackfan anemia (DBA) and physical findings suggestive of Treacher Collins syndrome or mandibulofacial dysostosis. In Family 2 a nonsense variant (p.R87*) in RPS26 was observed to segregate with an affected father and his two affected daughters (all affected with DBA). In Family 3 a de novo 3' splice site variant in RPS26, affecting the adenine in the conserved AG dinucleotide acceptor splice site of intron 1 was observed in a proband with DBA, hearing loss, cleft palate/uvula submucous celft, malar hypoplasia, VSD, diaphragmatic hernia, rental ectopia, and short stature. By RT-PCR analysis the splicing variant leads to loss of exon 2 (Figure S2). Of note, the proband in Family 3 was first reported by McFarren et al. (2007; PMID: 17483715). (PMID: 24942156) Chae et al. (2014) studied nine unrelated Korean patients with a clinical diagnosis of Diamond Blackfan Anemia (DBA). Using a combination of Sanger sequencing (for eight RP genes) and array the authors identified two probands with two distinct variants in RPS26; one being p.R87*. (PMID: 24675553) Quarello et al. (2012) performed MLPA testing on 72 unrelated Italian individuals with clinical diagnoses of Diamond-Blackfan anemia (DBA) that had previously tested negative on sequencing of the RPS19, RPS24, RPS26, RPL5,RPL11, RPS10, RPS14, RPS16, RPS17, or RPL35A. MLPA revealed deletions in 14 of the 72 patients, including 3 de novo deletions in RPS26. All gene copy number variations were confirmed by real-time PCR analysis. (PMID: 22689679) Farrar et al. (2011) used a genome-wide SNP array to identify deletions at known Diamond-Blackfan anemia (DBA) related loci in 9 of 51 patients with a clinical diagnosis of DBA and previously negative sequencing studies. Two deletions involving RPS26 were identified (Table 1). Patient ID1178 harbored a 15kb deletion which includes a portion of IKZF4 in addition to RPS26. Patient ID842 harbored an 85kb deletion which includes RPS26 and five additional genes. The inheritance status of these deletions is unknown. (PMID: 22045982) Doherty et al. (2010) used Sanger sequencing to identify variants in 35 ribosomal protein genes in 117 probands with Diamond-Blackfan anemia (DBA). Of the 117 probands 12 probands had 9 distinct variants in RPS26 (Table 3). One splice site variant (ISV1+1T>G of intron 2) was observed in one proband as a de novo variant (P17). Two distinct start codon variants among four probands (c.1A>G/T; p.M1V/L) were observed to either segregate with an affected father and affected son (P7 and P9) or to be de novo (P6 and P8). (PMID: 20116044)

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity