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Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes
  1. Ibrahim Ghemlas1,2,3,
  2. Hongbing Li1,
  3. Bozana Zlateska1,
  4. Robert Klaassen4,
  5. Conrad V Fernandez5,
  6. Rochelle A Yanofsky6,
  7. John Wu7,
  8. Yves Pastore8,
  9. Mariana Silva9,
  10. Jeff H Lipton10,
  11. Josee Brossard11,
  12. Bruno Michon12,
  13. Sharon Abish13,
  14. MacGregor Steele14,
  15. Roona Sinha15,
  16. Mark Belletrutti16,
  17. Vicky R Breakey17,
  18. Lawrence Jardine18,
  19. Lisa Goodyear19,
  20. Lillian Sung20,
  21. Santhosh Dhanraj1,21,
  22. Emma Reble1,
  23. Amanda Wagner2,
  24. Joseph Beyene22,
  25. Peter Ray1,23,
  26. Stephen Meyn1,
  27. Michaela Cada2,
  28. Yigal Dror1,2,21
  1. 1Program in Genetics and Genome Biology, Research Institute, Toronto, Ontario, Canada
  2. 2Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
  3. 3King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  4. 4Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
  5. 5IWK Health Centre, Halifax, Nova Scotia, Canada
  6. 6CancerCare Manitoba, Winnipeg, Manitoba, Canada
  7. 7British Columbia Children's Hospital, Vancouver, British Columbia, Canada
  8. 8Hôpital Ste. Justine, Montréal, Québec, Canada
  9. 9Queen's University, Kingston, Ontario, Canada
  10. 10Princess Margaret Hospital, Toronto, Ontario, Canada
  11. 11Centre hospitalier universitaire, Sherbrooke, Quebec, Canada
  12. 12Centre Hospital University Quebec-Pav CHUL, Sainte-Foy, Quebec, Canada
  13. 13Montreal Children's Hospital, Montreal, Québec, Canada
  14. 14Alberta Children's Hospital, Calgary, Alberta, Canada
  15. 15University of Saskatchewan, Saskatoon, Saskatchewan, Canada
  16. 16Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada
  17. 17McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada
  18. 18Children's Hospital at London Health Sciences Centre, London, Ontario, Canada
  19. 19Janeway Child Health Centre, St. John's, Newfoundland, Canada
  20. 20Population Health Sciences, Research Institute, The Hospital For Sick Children, Toronto, Ontario, Canada
  21. 21Faculty of Medicine, Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
  22. 22Program in Population Genomics, Department of Clinical Epidemiology & Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
  23. 23Molecular Genetic Laboratory, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
  1. Correspondence to Dr Yigal Dror, Division of Hematology/Oncology and Program in Genetics and Genome Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8; yigal.dror{at}


Background Phenotypic overlap among the inherited bone marrow failure syndromes (IBMFSs) frequently limits the ability to establish a diagnosis based solely on clinical features. >70 IBMFS genes have been identified, which often renders genetic testing prolonged and costly. Since correct diagnosis, treatment and cancer surveillance often depend on identifying the mutated gene, strategies that enable timely genotyping are essential.

Methods To overcome these challenges, we developed a next-generation sequencing assay to analyse a panel of 72 known IBMFS genes. Cases fulfilling the clinical diagnostic criteria of an IBMFS but without identified causal genotypes were included.

Results The assay was validated by detecting 52 variants previously found by Sanger sequencing. A total of 158 patients with unknown mutations were studied. Of 75 patients with known IBMFS categories (eg, Fanconi anaemia), 59% had causal mutations. Among 83 patients with unclassified IBMFSs, we found causal mutations and established the diagnosis in 18% of the patients. The assay detected mutant genes that had not previously been reported to be associated with the patient phenotypes. In other cases, the assay led to amendments of diagnoses. In 20% of genotype cases, the results indicated a cancer surveillance programme.

Conclusions The novel assay is efficient, accurate and has a major impact on patient care.

  • Clinical genetics
  • Diagnostics tests
  • Haematology (incl Blood transfusion)
  • Other oncology

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