Identifying Rare Mutations in Diamond-Blackfan Anemia Using Target Enrichment and Next-Generation Sequencing

Diamond-Blackfan anemia (DBA) is a rare congenital stem cell disorder associated with monoallelic inactivating mutations in the ribosomal protein (RP) genes. It leads to bone marrow failure syndrome by causing defects in erythroid progenitor and precursor cell development. Loss of function mutations in 10 of the c. 80 RP genes have been definitively associated with DBA. RPS19 is mutated in up to 25% of DBA cases, and 13 other RP genes are mutated in a further 25–35%. The molecular basis of the remaining 40–50% of cases is unknown. Since such cases may harbor mutations in one or more of the remaining RP genes and such mutations may occur at very low frequencies, genetic screening using conventional Sanger sequencing on a perexon/per-gene basis is challenging.