The Genetic Landscape of Diamond-Blackfan Anemia
Jacob C Ulirsch,
Jeffrey M. Verboon,
Michael H Guo,
Leif S Ludwig,
Robert E Handsaker,
Nour J Abdulhay,
Elaine T Lim,
Beryl B. Cummings,
Katherine R Chao,
Alan H Beggs,
Casie A Genetti,
Colin A Sieff,
Peter E Newburger,
Jeffrey M Lipton,
David J. Amor,
Steven A. McCarroll,
Anne H. O’Donnell-Luria,
Stacey B Gabriel,
Daniel G. MacArthur,
Eric S Lander,
Lydie Da Costa,
David G Nathan,
Andrei K Korostelev,
Vijay G Sankaran,
Hanna T Gazda
Posted 10 Jul 2018
bioRxiv DOI: 10.1101/365890 (published DOI: 10.1016/j.ajhg.2018.10.027)
Posted 10 Jul 2018
Diamond-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 patient-derived 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.
- Downloaded 1,004 times
- Download rankings, all-time:
- Site-wide: 9,225 out of 76,812
- In genetics: 670 out of 4,149
- Year to date:
- Site-wide: 36,391 out of 76,812
- Since beginning of last month:
- Site-wide: 42,966 out of 76,812
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!