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.
We analyzed 121 IBMFS patients using a targeted sequencing covering 184 associated genes and 250 IBMFS patients using whole-exome sequencing (WES).
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.
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
Fanconi anemia; inherited bone marrow failure; next-generation sequencing; target sequencing; whole-exome sequencing
- Inherited bone marrow failure syndromes in 2012. Int J Hematol 2013;97:20–29. , ,
- Stress and DNA repair biology of the Fanconi anemia pathway. Blood 2014;124:2812–2819. , , , ,
- Marrow failure: a window into ribosome biology. Blood 2014;124:2784–2792. ,
- Bone marrow failure and the telomeropathies. Blood 2014;124:2775–2783. , ,
- Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011;12:745–755. , , , et al.
- Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity. Haematologica 2015;100:42–48. , , , 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;52:575–584. , , , et al.
- ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008;10:294–300. , , , et al.; .
- An integrated map of genetic variation from 1,092 human genomes. Nature 2012;491:56–65. , , , et al.; .
- ACTN1 mutations cause congenital macrothrombocytopenia. Am J Hum Genet 2013;92:431–438. , , , et al.
- Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet 2013;45:937–941. , , , et al.
- Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 1999;23:166–175. , , , et al.
- Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Blood 2012;119:3815–3819. , , , ,
- Cancer in dyskeratosis congenita. Blood 2009;113:6549–6557. , , ,
- A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood 2003;101:1249–1256. , , , et al.
- Variable clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry. J Pediatr 2014;164:866–870. , , , et al.
- Severe congenital neutropenia. Hematol Oncol Clin North Am 2009;23:307–320. ,
- Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res 2015;25:305–315. , , , et al.
- Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. Blood 2013;121:e138–e148. , , , et al.; .
- Loss of function mutations in RPL27 and RPS27 identified by whole-exome sequencing in Diamond-Blackfan anaemia. Br J Haematol 2015;168:854–864. , , , et al.
- Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia. Am J Hum Genet 2015;96:1001–1007 , , , et al.