title: Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes.
abstract: 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.
authors.affiliation: Program in Genetics and Genome Biology, Research Institute, Toronto, Ontario, Canada Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Ghemlas
authors.affiliation: Program in Genetics and Genome Biology, Research Institute, Toronto, Ontario, Canada.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Li
authors.affiliation: Program in Genetics and Genome Biology, Research Institute, Toronto, Ontario, Canada.
authors.forename: Bozana
authors.initials: B
authors.lastname: Zlateska
authors.affiliation: Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Klaassen
authors.affiliation: IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: Conrad V
authors.initials: CV
authors.lastname: Fernandez
authors.affiliation: CancerCare Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Rochelle A
authors.initials: RA
authors.lastname: Yanofsky
authors.affiliation: British Columbia Children's Hospital, Vancouver, British Columbia, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Wu
authors.affiliation: Hôpital Ste. Justine, Montréal, Québec, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pastore
authors.affiliation: Queen's University, Kingston, Ontario, Canada.
authors.forename: Mariana
authors.initials: M
authors.lastname: Silva
authors.affiliation: Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: Jeff H
authors.initials: JH
authors.lastname: Lipton
authors.affiliation: Centre hospitalier universitaire, Sherbrooke, Quebec, Canada.
authors.forename: Josee
authors.initials: J
authors.lastname: Brossard
authors.affiliation: Centre Hospital University Quebec-Pav CHUL, Sainte-Foy, Quebec, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Michon
authors.affiliation: Montreal Children's Hospital, Montreal, Québec, Canada.
authors.forename: Sharon
authors.initials: S
authors.lastname: Abish
authors.affiliation: Alberta Children's Hospital, Calgary, Alberta, Canada.
authors.forename: MacGregor
authors.initials: M
authors.lastname: Steele
authors.affiliation: University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Roona
authors.initials: R
authors.lastname: Sinha
authors.affiliation: Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Belletrutti
authors.affiliation: McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Vicky R
authors.initials: VR
authors.lastname: Breakey
authors.affiliation: Children's Hospital at London Health Sciences Centre, London, Ontario, Canada.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Jardine
authors.affiliation: Janeway Child Health Centre, St. John's, Newfoundland, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Goodyear
authors.affiliation: Population Health Sciences, Research Institute, The Hospital For Sick Children, Toronto, Ontario, Canada.
authors.forename: Lillian
authors.initials: L
authors.lastname: Sung
authors.affiliation: Program in Genetics and Genome Biology, Research Institute, Toronto, Ontario, Canada Faculty of Medicine, Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Dhanraj
authors.affiliation: Program in Genetics and Genome Biology, Research Institute, Toronto, Ontario, Canada.
authors.forename: Emma
authors.initials: E
authors.lastname: Reble
authors.affiliation: Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Program in Population Genomics, Department of Clinical Epidemiology & Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Beyene
authors.affiliation: Program in Genetics and Genome Biology, Research Institute, Toronto, Ontario, Canada Molecular Genetic Laboratory, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Ray
authors.affiliation: Program in Genetics and Genome Biology, Research Institute, Toronto, Ontario, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Meyn
authors.affiliation: Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Michaela
authors.initials: M
authors.lastname: Cada
authors.affiliation: Program in Genetics and Genome Biology, Research Institute, Toronto, Ontario, Canada Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada Faculty of Medicine, Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yigal
authors.initials: Y
authors.lastname: Dror
mesh_terms: D000741:Anemia, Aplastic; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D006457:Hemoglobinuria, Paroxysmal / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D009154:Mutation; D005791:Patient Care; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA / Q000379:methods*
keywords: Clinical genetics; Diagnostics tests; Haematology (incl Blood transfusion); Other oncology