The Genetic Landscape of Diamond-Blackfan Anemia

Jacob C. Ulirsch, Jeffrey M. Verboon, Shideh Kazerounian, Michael H. Guo, Daniel Yuan, Leif S. Ludwig, Robert E. Handsaker, Nour J. Abdulhay, Claudia Fiorini, Giulio Genovese, Elaine T. Lim, Aaron Cheng, Beryl B. Cummings, Katherine R. Chao, Alan H. Beggs, Casie A. Genetti, Colin A. Sieff, Peter E. Newburger, Edyta Niewiadomska, Michal MatysiakAdrianna Vlachos, Jeffrey M. Lipton, Eva Atsidaftos, Bertil Glader, Anupama Narla, Pierre Emmanuel Gleizes, Marie Françoise O'Donohue, Nathalie Montel-Lehry, David J. Amor, Steven A. McCarroll, Anne H. O'Donnell-Luria, Namrata Gupta, Stacey B. Gabriel, Daniel G. MacArthur, Eric S. Lander, Monkol Lek, Lydie Da Costa, David G. Nathan, Andrei A. Korostelev, Ron Do, Vijay G. Sankaran, Hanna T. Gazda

Research output: Contribution to journalArticlepeer-review

159 Scopus citations


Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine 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-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.

Original languageEnglish
Pages (from-to)930-947
Number of pages18
JournalAmerican Journal of Human Genetics
Issue number6
StatePublished - 6 Dec 2018


  • Diamond-Blackfan anemia
  • RNA sequencing
  • congenital hypoplastic anemia
  • hematopoiesis
  • human genetics
  • rare disease
  • whole-exome sequencing


Dive into the research topics of 'The Genetic Landscape of Diamond-Blackfan Anemia'. Together they form a unique fingerprint.

Cite this