Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes

Journal name:
Genetics in Medicine
(2017)
DOI:
doi:10.1038/gim.2016.197
Received
Accepted
Published online

Abstract

Purpose:

Precise genetic diagnosis of inherited bone marrow failure syndromes (IBMFS), a heterogeneous group of genetic disorders, is challenging but essential for precise clinical decision making.

Methods:

We analyzed 121 IBMFS patients using a targeted sequencing covering 184 associated genes and 250 IBMFS patients using whole-exome sequencing (WES).

Results:

We achieved successful genetic diagnoses for 53 of 121 patients (44%) using targeted sequencing and for 68 of 250 patients (27%) using WES. In the majority of cases (targeted sequencing: 45/53, 85%; WES: 63/68, 93%), the detected variants were concordant with, and therefore supported, the clinical diagnoses. However, in the remaining 13 cases (8 patients by target sequencing and 5 patients by WES), the clinical diagnoses were incompatible with the detected variants.

Conclusion:

Our approach utilizing targeted sequencing and WES achieved satisfactory diagnostic rates and supported the efficacy of massive parallel sequencing as a diagnostic tool for IBMFS.

Genet Med advance online publication 19 January 2017

Keywords:

Fanconi anemia; inherited bone marrow failure; next-generation sequencing; target sequencing; whole-exome sequencing

References

  1. Sakaguchi H, Nakanishi K, Kojima S. Inherited bone marrow failure syndromes in 2012. Int J Hematol 2013;97:2029.
  2. Longerich S, Li J, Xiong Y, Sung P, Kupfer GM. Stress and DNA repair biology of the Fanconi anemia pathway. Blood 2014;124:28122819.
  3. Ruggero D, Shimamura A. Marrow failure: a window into ribosome biology. Blood 2014;124:27842792.
  4. Townsley DM, Dumitriu B, Young NS. Bone marrow failure and the telomeropathies. Blood 2014;124:27752783.
  5. Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011;12:745755.
  6. Zhang MY, Keel SB, Walsh T, et al. Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity. Haematologica 2015;100:4248.
  7. Ghemlas I, Li H, Zlateska B, et al. Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes. J Med Genet 2015;52:575584.
  8. Richards CS, Bale S, Bellissimo DB, et al.; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee. ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008;10:294300.
  9. Abecasis GR, Auton A, Brooks LD, et al.; 1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 2012;491:5665.
  10. Kunishima S, Okuno Y, Yoshida K, et al. ACTN1 mutations cause congenital macrothrombocytopenia. Am J Hum Genet 2013;92:431438.
  11. Sakaguchi H, Okuno Y, Muramatsu H, et al. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet 2013;45:937941.
  12. Song WJ, Sullivan MG, Legare RD, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 1999;23:166175.
  13. 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;119:38153819.
  14. Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in dyskeratosis congenita. Blood 2009;113:65496557.
  15. Kutler DI, Singh B, Satagopan J, et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood 2003;101:12491256.
  16. Myers KC, Bolyard AA, Otto B, et al. Variable clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry. J Pediatr 2014;164:866870.
  17. Welte K, Zeidler C. Severe congenital neutropenia. Hematol Oncol Clin North Am 2009;23:307320.
  18. Amendola LM, Dorschner MO, Robertson PD, et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res 2015;25:305315.
  19. Chandrasekharappa SC, Lach FP, Kimble DC, et al.; NISC Comparative Sequencing Program. Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. Blood 2013;121:e138e148.
  20. Wang R, Yoshida K, Toki T, et al. Loss of function mutations in RPL27 and RPS27 identified by whole-exome sequencing in Diamond-Blackfan anaemia. Br J Haematol 2015;168:854864.
  21. Hira A, Yoshida K, Sato K, et al. Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia. Am J Hum Genet 2015;96:10011007

Download references

Author information

  1. The first three authors contributed equally to this work.

    • Hideki Muramatsu,
    • Yusuke Okuno &
    • Kenichi Yoshida

Affiliations

  1. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    • Hideki Muramatsu,
    • Yusuke Okuno,
    • Sayoko Doisaki,
    • Atsushi Narita,
    • Hirotoshi Sakaguchi,
    • Nozomu Kawashima,
    • Xinan Wang,
    • Yinyan Xu,
    • Asahito Hama,
    • Yoshiyuki Takahashi &
    • Seiji Kojima
  2. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    • Kenichi Yoshida,
    • Masashi Sanada &
    • Seishi Ogawa
  3. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    • Yuichi Shiraishi,
    • Kenichi Chiba,
    • Hiroko Tanaka &
    • Satoru Miyano
  4. Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    • Masashi Sanada &
    • Shinji Kunishima
  5. Department of Transfusion Medicine and Cell Processing, Tokyo Women’s Medical University, Tokyo, Japan

    • Hitoshi Kanno
  6. Department of Hematology, Nippon Medical School, Tokyo, Japan

    • Hiroki Yamaguchi
  7. Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan

    • Shouichi Ohga
  8. Department of Pediatrics, St. Luke’s International Hospital, Tokyo, Japan

    • Atsushi Manabe
  9. Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai, Japan

    • Hideo Harigae
  10. Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan

    • Eiichi Ishii
  11. Department of Pediatrics, Hiroshima University Hospital, Hiroshima, Japan

    • Masao Kobayashi
  12. Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan

    • Kenichi Koike
  13. Department of Hematology/Oncology, Shizuoka Children’s Hospital, Shizuoka, Japan

    • Kenichiro Watanabe
  14. Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    • Etsuro Ito
  15. Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan

    • Minoru Takata
  16. Department of Cell Transplantation and Regenerative Medicine, Tokai University Hospital, Isehara, Japan

    • Miharu Yabe
  17. Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    • Satoru Miyano

Corresponding author

Correspondence to:

Author details

Supplementary information

Additional data