Skip to main content

Advertisement

Log in

Diagnostic challenge of Diamond–Blackfan anemia in mothers and children by whole-exome sequencing

International Journal of Hematology Aims and scope Submit manuscript

Abstract

Diamond–Blackfan anemia (DBA) is a pure red cell aplasia that arises from defective ribosomal proteins (RPs). Patients with this rare ribosomopathy present with neonatal anemia and occasional dysmorphism. Clinical heterogeneity and clusters of causative RP genes hamper the diagnosis and perinatal management. We report three mother-and-child pairs of anemia who were finally diagnosed by whole-exome sequencing. Each pair showed distinct disease severity and response to anemia treatment. Only one mother had the diagnostic dysmorphism, including short stature, webbed neck, and thenar hypoplasia. This mother had a frame-shift mutation of RPL11 (exon 3, c.58_59del). Her infant showed transient neonatal anemia, but had no mutations of RP genes. The other mother–child pairs had a missense mutation of RPS19 (exon 4, c.185G>A), and a splicing error of RPS7 (exon 3, c.76-1G>T), respectively. Other than the reported mutations, there were no variants in genes significantly associated with anemia. Our results suggested that whole-exome sequencing (WES) is effective for achieving a prompt and correct diagnosis of human ribosomopathy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

WES:

whole-exome sequencing

DBA:

Diamond–Blackfan anemia

RP:

ribosomal protein

References

  1. Lipton JM, Atsidaftos E, Zyskind I, Vlachos A. Improving clinical care and elucidating the pathophysiology of Diamond Blackfan anemia: an update from the Diamond Blackfan Anemia Registry. Pediatr Blood Cancer. 2006;46(5):558–64.

    Article  PubMed  Google Scholar 

  2. Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, Ramenghi U, et al. Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haematol. 2008;142(6):859–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vlachos A, Rosenberg PS, Atsidaftos E, Alter BP, Lipton JM. Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Blood. 2012;119(16):3815–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Draptchinskaia N, Gustavsson P, Andersson B, Pettersson M, Willig TN, Dianzani I, et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet. 1999;21(2):169–75.

    Article  CAS  PubMed  Google Scholar 

  5. Gazda HT, Grabowska A, Merida-Long LB, Latawiec E, Schneider HE, Lipton JM, et al. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2006;79(6):1110–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cmejla R, Cmejlova J, Handrkova H, Petrak J, Pospisilova D. Ribosomal protein S17 gene (RPS17) is mutated in Diamond-Blackfan anemia. Hum Mutat. 2007;28(12):1178–82.

    Article  CAS  PubMed  Google Scholar 

  7. Farrar JE, Nater M, Caywood E, McDevitt MA, Kowalski J, Takemoto CM, et al. Abnormalities of the large ribosomal subunit protein, Rpl35a. Diamond-Blackfan anemia. Blood. 2008;112(5):1582–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gazda HT, Sheen MR, Vlachos A, Choesmel V, O’Donohue MF, Schneider H, et al. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008;83(6):769–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Doherty L, Sheen MR, Vlachos A, Choesmel V, O’Donohue MF, Clinton C, et al. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2010;86(2):222–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Konno Y, Toki T, Tandai S, Xu G, Wang R, Terui K, et al. Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan anemia. Haematologica. 2010;95(8):1293–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gazda HT, Preti M, Sheen MR, O’Donohue MF, Vlachos A, Davies SM, et al. Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in Diamond-Blackfan anemia. Hum Mutat. 2012;33(7):1037–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gerrard G, Valgañón M, Foong HE, Kasperaviciute D, Iskander D, Game L, et al. Target enrichment and high throughput sequencing of 80 ribosomal protein genes to identify mutations associated with Diamond-Blackfan anaemia. Br J Haematol. 2013;162(4):530–6.

    Article  CAS  PubMed  Google Scholar 

  13. Wang R, Yoshida K, Toki T, Sawada T, Uechi T, Okuno Y, et al. Loss of function mutations in RPL27 and RPS27 identified by whole-exome sequencing in Diamond-Blackfan anaemia. Br J Haematol. 2015;168(6):854–64.

    Article  CAS  PubMed  Google Scholar 

  14. Kuramitsu M, Sato-Otsubo A, Morio T, Takagi M, Toki T, Terui K, et al. Extensive gene deletions in Japanese patients with Diamond-Blackfan anemia. Blood. 2012;119(10):2376–84.

    Article  CAS  PubMed  Google Scholar 

  15. Sankaran VG, Ghazvinian R, Do R, Thiru P, Vergilio JA, Beggs AH, et al. Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. J Clin Invest. 2012;122(7):2439–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bibikova E, Youn MY, Danilova N, Ono-Uruga Y, Konto-Ghiorghi Y, Ochoa R, et al. TNF-mediated inflammation represses GATA1 and activates p38 MAP kinase in RPS19-deficient hematopoietic progenitors. Blood. 2014;124(25):3791–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dutt S, Narla A, Lin K, Mullally A, Abayasekara N, Megerdichian C, et al. Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. Blood. 2011;117(9):2567–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Torihara H, Uechi T, Chakraborty A, Shinya M, Sakai N, Kenmochi N. Erythropoiesis failure due to RPS19 deficiency is independent of an activated Tp53 response in a zebrafish model of Diamond-Blackfan anaemia. Br J Haematol. 2011;152(5):648–54.

    Article  CAS  PubMed  Google Scholar 

  19. Utsugisawa T, Uchiyama T, Toki T, Ogura H, Aoki T, Hamaguchi I, et al. Erythrocyte glutathione is a novel biomarker of Diamond-Blackfan anemia. Blood Cells Mol Dis. 2016;59:31–6.

    Article  CAS  PubMed  Google Scholar 

  20. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478(7367):64–9.

    Article  CAS  PubMed  Google Scholar 

  21. Kunishima S, Okuno Y, Yoshida K, Shiraishi Y, Sanada M, Muramatsu H, et al. ACTN1 mutations cause congenital macrothrombocytopenia. Am J Hum Genet. 2013;92(3):431–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fargo JH, Kratz CP, Giri N, Savage SA, Wong C, Backer K, et al. Erythrocyte adenosine deaminase: diagnostic value for Diamond-Blackfan anaemia. Br J Haematol. 2013;160(4):547–54.

    Article  CAS  PubMed  Google Scholar 

  23. Iolascon A, Heimpel H, Wahlin A, Tamary H. Congenital dyserythropoietic anemias: molecular insights and diagnostic approach. Blood. 2013;122(13):2162–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. van den Akker M, Dror Y, Odame I. Transient erythroblastopenia of childhood is an underdiagnosed and self-limiting disease. Acta Paediatr. 2014;103(7):e288–94.

    PubMed  Google Scholar 

  25. Ito E, Konno Y, Toki T, Terui K. Molecular pathogenesis in Diamond-Blackfan anemia. Int J Hematol. 2010;92(3):413–8.

    Article  CAS  PubMed  Google Scholar 

  26. Mirabello L, Macari ER, Jessop L, Ellis SR, Myers T, Giri N, et al. Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families. Blood. 2014;124(1):24–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Giri G, Kang E, Tisdale JF, Follman D, Rivera M, Schwartz GN, et al. Clinical and laboratory evidence for a trilineage haematopoietic defect in patients with refractory Diamond-Blackfan anaemia. Br J Haematol. 2000;108(1):167–75.

    Article  CAS  PubMed  Google Scholar 

  28. Narla A, Ebert BL. Ribosomopathies: human disorders of ribosome dysfunction. Blood. 2010;115(16):3196–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ohga S, Mugishima H, Ohara A, Kojima S, Fujisawa K, Yagi K, et al. Diamond-Blackfan anemia in Japan: clinical outcomes of prednisolone therapy and hematopoietic stem cell transplantation. Int J Hematol. 2004;79(1):22–3.

    Article  PubMed  Google Scholar 

  30. Huh WW, Gill J, Sheth S, Buchanan GR. Pneumocystis carinii pneumonia in patients with Diamond-Blackfan anemia receiving high-dose corticosteroids. J Pediatr Hematol Oncol. 2002;24(5):410–2.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Yoshihiro Azuma (Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan) and Prof. Yukio Tanizawa (Third Department of Internal Medicine, Yamaguchi University Graduate School of Medicine, Ube, Japan) for the clinical management and useful suggestions. We also thank Dr. Brian Quinn (Editor-in-Chief. Japan Medical Communication) for editing the manuscript. This work was supported by a “Research on Measures for Intractable Diseases” Project (H23-012): matching fund subsidy from the Ministry of Health Labour and Welfare of Japan, and Grants-in-Aid for Scientific Research (Research on Intractable Diseases) from the Ministry of Health, Labour and Welfare of Japan (H23-029).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shouichi Ohga.

Ethics declarations

Conflict of interest

The authors declared no conflicts of interest in association with this study.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ichimura, T., Yoshida, K., Okuno, Y. et al. Diagnostic challenge of Diamond–Blackfan anemia in mothers and children by whole-exome sequencing. Int J Hematol 105, 515–520 (2017). https://doi.org/10.1007/s12185-016-2151-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-016-2151-7

Keywords

Navigation