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J Med Genet. 2015 Sep;52(9):575-84. doi: 10.1136/jmedgenet-2015-103270. Epub 2015 Jul 1.

Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes.

Author information

1
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.
2
Program in Genetics and Genome Biology, Research Institute, Toronto, Ontario, Canada.
3
Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
4
IWK Health Centre, Halifax, Nova Scotia, Canada.
5
CancerCare Manitoba, Winnipeg, Manitoba, Canada.
6
British Columbia Children's Hospital, Vancouver, British Columbia, Canada.
7
Hôpital Ste. Justine, Montréal, Québec, Canada.
8
Queen's University, Kingston, Ontario, Canada.
9
Princess Margaret Hospital, Toronto, Ontario, Canada.
10
Centre hospitalier universitaire, Sherbrooke, Quebec, Canada.
11
Centre Hospital University Quebec-Pav CHUL, Sainte-Foy, Quebec, Canada.
12
Montreal Children's Hospital, Montreal, Québec, Canada.
13
Alberta Children's Hospital, Calgary, Alberta, Canada.
14
University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
15
Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada.
16
McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada.
17
Children's Hospital at London Health Sciences Centre, London, Ontario, Canada.
18
Janeway Child Health Centre, St. John's, Newfoundland, Canada.
19
Population Health Sciences, Research Institute, The Hospital For Sick Children, Toronto, Ontario, Canada.
20
Program in Genetics and Genome Biology, Research Institute, Toronto, Ontario, Canada Faculty of Medicine, Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
21
Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
22
Program in Population Genomics, Department of Clinical Epidemiology & Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
23
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.
24
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.

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.

KEYWORDS:

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

PMID:
26136524
DOI:
10.1136/jmedgenet-2015-103270
[Indexed for MEDLINE]

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