The Genetic Landscape of Diamond-Blackfan Anemia
Author:
Ulirsch Jacob C., Verboon Jeffrey M., Kazerounian Shideh, Guo Michael H., Yuan Daniel, Ludwig Leif S., Handsaker Robert E., Abdulhay Nour J., Fiorini Claudia, Genovese Giulio, Lim Elaine T., Cheng Aaron, Cummings Beryl B., Chao Katherine R., Beggs Alan H., Genetti Casie A., Sieff Colin A., Newburger Peter E., Niewiadomska Edyta, Matysiak Michal, Vlachos Adrianna, Lipton Jeffrey M., Atsidaftos Eva, Glader Bertil, Narla Anupama, Gleizes Pierre-Emmanuel, O’Donohue Marie-Françoise, Montel-Lehry Nathalie, Amor David J., McCarroll Steven A., O’Donnell-Luria Anne H., Gupta Namrata, Gabriel Stacey B., MacArthur Daniel G., Lander Eric S., Lek Monkol, Da Costa Lydie, Nathan David. G., Korostelev Andrei K., Do Ron, Sankaran Vijay G.ORCID, Gazda Hanna T.
Abstract
ABSTRACTDiamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 1 in 100,000 to 200,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this genetically heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole exome sequencing (WES). Overall, we identified rare and predicted damaging mutations in likely causal genes for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and in one of 19 previously reported genes encoding for a diverse set of ribosomal proteins (RPs). Using WES exon coverage estimates, we were able to identify and validate 31 deletions in DBA associated genes. We also observed an enrichment for extended splice site mutations and validated the diverse effects of these mutations using RNA sequencing in patientderived cell lines. Leveraging the size of our cohort, we observed several robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. In addition to comprehensively identifying mutations in known genes, we further identified rare mutations in 7 previously unreported RP genes that may cause DBA. We also identified several distinct disorders that appear to phenocopy DBA, including 9 individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain > 5% of DBA cases. Overall, this comprehensive report should not only inform clinical practice for DBA patients, but also the design and analysis of future rare variant studies for heterogeneous Mendelian disorders.
Publisher
Cold Spring Harbor Laboratory
Cited by
2 articles.
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