The genetic landscape of diamond-blackfan anemia

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Item Type:	Article
Title:	The genetic landscape of diamond-blackfan anemia
Creators Name:	Ulirsch, J.C., Verboon, J.M., Kazerounian, S., Guo, M.H., Yuan, D., Ludwig, L.S., Handsaker, R.E., Abdulhay, N.J., Fiorini, C., Genovese, G., Lim, E.T., Cheng, A., Cummings, B.B., Chao, K.R., Beggs, A.H., Genetti, C.A., Sieff, C.A., Newburger, P.E., Niewiadomska, E., Matysiak, M., Vlachos, A., Lipton, J.M., Atsidaftos, E., Glader, B., Narla, A., Gleizes, P.E., O'Donohue, M.F., Montel-Lehry, N., Amor, D.J., McCarroll, S.A., O'Donnell-Luria, A.H., Gupta, N., Gabriel, S.B., MacArthur, D.G., Lander, E.S., Lek, M., Da Costa, L., Nathan, D.G., Korostelev, A.A., Do, R., Sankaran, V.G. and Gazda, H.T.
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.
Keywords:	Human Genetics, Rare Disease, Whole-Exome Sequencing, Congenital Hypoplastic Anemia, Diamond-Blackfan Anemia, RNA Sequencing, Hematopoiesis
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	103
Number:	6
Page Range:	930-947
Date:	6 December 2018
Additional Information:	Erratum in: Am J Hum Genet 104(2):356
Official Publication:	https://doi.org/10.1016/j.ajhg.2018.10.027
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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