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Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation
  1. Lisa Mirabello1,
  2. Payal P Khincha1,
  3. Steven R Ellis2,
  4. Neelam Giri1,
  5. Seth Brodie3,
  6. Settara C Chandrasekharappa4,
  7. Frank X Donovan4,
  8. Weiyin Zhou3,
  9. Belynda D Hicks1,3,
  10. Joseph F Boland1,3,
  11. Meredith Yeager1,3,
  12. Kristine Jones3,
  13. Bin Zhu3,
  14. Mingyi Wang3,
  15. Blanche P Alter1,
  16. Sharon A Savage1
  1. 1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
  2. 2 Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky, USA
  3. 3 Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
  4. 4 Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA
  1. Correspondence to Dr Sharon A Savage, Clinical Genetics Branch Division of Cancer Epidemiology and Genetics National Cancer Institute 9609 Medical Center Dr, Rm. 6E454, Bethesda, MD 20892, USA; savagesh{at}


Background Diamond-Blackfan anaemia (DBA) is an inherited bone marrow failure syndrome (IBMFS) characterised by erythroid hypoplasia. It is associated with congenital anomalies and a high risk of developing specific cancers. DBA is caused predominantly by autosomal dominant pathogenic variants in at least 15 genes affecting ribosomal biogenesis and function. Two X-linked recessive genes have been identified.

Objectives We aim to identify the genetic aetiology of DBA.

Methods Of 87 families with DBA enrolled in an institutional review board-approved cohort study ( Identifier:NCT00027274), 61 had genetic testing information available. Thirty-five families did not have a known genetic cause and thus underwent comprehensive genomic evaluation with whole exome sequencing, deletion and CNV analyses to identify their disease-associated pathogenic variant. Controls for functional studies were healthy mutation-negative individuals enrolled in the same study.

Results Our analyses uncovered heterozygous pathogenic variants in two previously undescribed genes in two families. One family had a non-synonymous variant (p.K77N) in RPL35; the second family had a non-synonymous variant (p. L51S) in RPL18. Both of these variants result in pre-rRNA processing defects. We identified heterozygous pathogenic variants in previously known DBA genes in 16 of 35 families. Seventeen families who underwent genetic analyses are yet to have a genetic cause of disease identified.

Conclusions Overall, heterozygous pathogenic variants in ribosomal genes were identified in 44 of the 61 families (72%). De novo pathogenic variants were observed in 57% of patients with DBA. Ongoing studies of DBA genomics will be important to understand this complex disorder.

  • Diamond-Blackfan anemia
  • whole exome sequencing
  • genetics
  • RPL18
  • RPL35
  • ribosome

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  • An abstract of this study was presented as poster at the 2016 American Society of Hematology Annual Meeting, San Diego, California, USA

  • Acknowledgements The authors thank all of the study participants for their valuable contributions. Lisa Leathwood, RN, Maureen Risch, RN, and Ann Carr, CGC of Westat, provided excellent study support.

  • Contributors Project design was carried out by SAS and LM. Analyses were performed by LM. Clinical characterisation and sample collection was performed by PK, NG and BPA. Sequencing and validation was performed by BDH, BZ, MW, KJ, MY, JFB and the NCI DCEG Cancer Genomics Research Laboratory. Cell culture assays were performed by SB. CNV analysis was performed by WZ, FXD and SCC. Pre-rRNA processing was performed by SRE. The manuscript was written by LM, PK and SAS and reviewed and approved by all coauthors.

  • Funding This study was funded, in part, by the intramural research programme of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health and by contracts N02-CP-91026, N02-CP-11019 and HHSN261200655001C with Westat. SCC

    and FXD acknowledge research support from the Intramural Research Program of National Human Genome Research Institute, National Institutes of Health.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Collaborators NCI DCEG Cancer Genomics Research Laboratory including Sara Bass, Laurie Burdett, Salma Chowdhury, Michael Cullen, Casey Dagnall, Rebecca Eggebeen, Herbert Higson, Amy A Hutchinson, Sally Larson, Kerrie Lashley, Hyo Jung Lee, Wen Luo, Michael Malasky, Michelle Manning, Jason Mitchell, Adri O’Neil, David Roberson, Shalabh Suman, Aurelie Vogt, and Kathleen Wyatt. NCI DCEG Cancer Sequencing Working Group including Neil E Caporaso, Stephen J Chanock, Mark H Greene, Lynn R Goldin, Alisa M Goldstein, Allan Hildesheim, Nan Hu, Maria Teresa Landi, Jennifer Loud, Phuong L Mai, Mary L McMaster, Lindsay Morton, Dilys Parry, Melissa Rotunno, Douglas R Stewart, Phil Taylor, Geoffrey S Tobias, Margaret A Tucker, Xiaohong R Yang, and Guoqin Yu.

  • Correction notice This article has been updated since it published online first. Erroneous symbols appearing in Figure 2 have been deleted and Figure 2 legend has been updated to ensure the consistency of reference to NCI-172.