The Genetic Landscape of Diamond-Blackfan Anemia

UMMS Affiliation

Department of Pediatrics; RNA Therapeutics Institute; Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetic Phenomena | Genetics and Genomics | Hematology | Hemic and Immune Systems | Hemic and Lymphatic Diseases | Medical Genetics | Nucleic Acids, Nucleotides, and Nucleosides | Pediatrics


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.


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

DOI of Published Version



Am J Hum Genet. 2018 Dec 6;103(6):930-947. doi: 10.1016/j.ajhg.2018.10.027. Epub 2018 Nov 29. Link to article on publisher's site

Journal/Book/Conference Title

American journal of human genetics


Full author list omitted for brevity. For the full list of authors, see article.

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