The Genetic Landscape of Diamond-Blackfan Anemia
Author(s)
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
Date Issued
December 2018
Journal
American Journal of Human Genetics
Publisher
Elsevier BV
Citation
Ulirsch, Jacob C. et al. "The Genetic Landscape of Diamond-Blackfan Anemia." American Journal of Human Genetics 103, 6 (December 2018): P930-947 © 2018 American Society of Human Genetics
Version
Author's final manuscript
Abstract
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.
MIT Department
Broad Institute of MIT and Harvard
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.ajhg.2018.10.027
