Introduction Inherited bone marrow failure syndromes (IBMFSs) often have substantial phenotypic overlap, thus genotyping is often critical for establishing a diagnosis.
Objectives and methods To determine the genetic characteristics and mutation profiles of IBMFSs, a comprehensive population-based study that prospectively enrols all typical and atypical cases without bias is required. The Canadian Inherited Marrow Failure Study is such a study, and was used to extract clinical and genetic information for patients enrolled up to May 2010.
Results Among the 259 primary patients with IBMFS enrolled in the study, the most prevalent categories were Diamond–Blackfan anaemia (44 patients), Fanconi anaemia (39) and Shwachman–Diamond syndrome (35). The estimated incidence of the primary IBMFSs was 64.5 per 106 births, with Fanconi anaemia having the highest incidence (11.4 cases per 106 births). A large number of patients (70) had haematological and non-haematological features that did not fulfil the diagnostic criteria of any specific IBMFS category. Disease-causing mutations were identified in 53.5% of the 142 patients tested, and in 16 different genes. Ten novel mutations in SBDS, RPL5, FANCA, FANCG, MPL and G6PT were identified. The most common mutations were nonsense (31 alleles) and splice site (28). Genetic heterogeneity of most IBMFSs was evident; however, the most commonly mutated gene was SBDS, followed by FANCA and RPS19.
Conclusion From this the largest published comprehensive cohort of IBMFSs, it can be concluded that recent advances have led to successful genotyping of about half of the patients. Establishing a genetic diagnosis is still challenging and there is a critical need to develop novel diagnostic tools.
- Inherited bone marrow failure syndromes
- aplastic anaemia
- myelodysplastic syndrome
- clinical genetics
- genetic screening/counselling
- haematology (incl blood transfusion)
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Funding Fanconi Anemia Canada, PO Box 38157, Toronto, Ontario M5N 3A92. C17 Canadian Research Network and Candlelighters Canada, 8308 - 114 Street, Edmonton, AB T6G 2E13. Neutropenia Support Association Inc, PO Box 243, 971 CorydonWinnipeg, Manitoba, Canada, R3M 3S74. Amgen Inc Canada, 6775 Financial Drive, Suite 100, Mississauga, Ontario L5N 0A4.
Competing interests None.
Ethics approval This study was conducted with the approval of the research ethics board at the Hospital for Sick Children and other contributing centres.
Provenance and peer review Not commissioned; externally peer reviewed.