The Genetic Landscape of Diamond-Blackfan Anemia
| Autor: | Aaron Cheng, David J. Amor, Colin A. Sieff, Nour J. Abdulhay, Claudia Fiorini, David G. Nathan, Beryl B. Cummings, Bertil Glader, Leif S. Ludwig, Peter E. Newburger, Stacey Gabriel, Giulio Genovese, Anupama Narla, Daniel G. MacArthur, Shideh Kazerounian, Alan H. Beggs, Edyta Niewiadomska, Namrata Gupta, Elaine T. Lim, Ron Do, Adrianna Vlachos, Casie A. Genetti, Katherine R. Chao, Pierre-Emmanuel Gleizes, Jeffrey M. Verboon, Jeffrey M. Lipton, Hanna T. Gazda, Lydie Da Costa, Jacob C. Ulirsch, Andrei A. Korostelev, Robert E. Handsaker, Eric S. Lander, Daniel Yuan, Steven A. McCarroll, Michał Matysiak, Vijay G. Sankaran, Monkol Lek, Michael H. Guo, Eva Atsidaftos, Anne H. O’Donnell-Luria, Marie-Françoise O'Donohue, Nathalie Montel-Lehry |
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| Přispěvatelé: | Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Harvard Medical School [Boston] (HMS), Duke University [Durham], Boston Children's Hospital, Laboratory of Human Genetics of Infectious Diseases, The Feinstein Institute for Medical Research, Laboratoire de biologie moléculaire eucaryote (LBME), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Murdoch Children's Research Institute (MCRI), Stanley Center for Psychiatric Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Massachusetts Institute of Technology (MIT), Department of Neuroscience, Uppsala University, AP-HP, Service d'Hématologie Biologique, Hôpital Robert-Debré, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Biology |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine [SDV]Life Sciences [q-bio] Cohort Studies Exon 0302 clinical medicine Exome Diamond–Blackfan anemia Child Genetics (clinical) Exome sequencing ComputingMilieux_MISCELLANEOUS Anemia Diamond-Blackfan Genetics 0303 health sciences education.field_of_study Exons 3. Good health Phenotype Child Preschool 030220 oncology & carcinogenesis Intercellular Signaling Peptides and Proteins Female Ribosomal Proteins Adolescent Sequence analysis Population Biology Article 03 medical and health sciences Exome Sequencing medicine Humans education Gene Genetic Association Studies Loss function 030304 developmental biology Phenocopy Sequence Analysis RNA Genetic heterogeneity Correction medicine.disease Human genetics 030104 developmental biology Mutation Ribosomes Gene Deletion [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Zdroj: | American Journal of Human Genetics American Journal of Human Genetics, Elsevier (Cell Press), 2018, 103 (6), pp.930-947. ⟨10.1016/j.ajhg.2018.10.027⟩ Prof. Lander via Courtney Crummett |
| ISSN: | 0002-9297 1537-6605 |
| DOI: | 10.1016/j.ajhg.2018.10.027⟩ |
| Popis: | 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 patientderived 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 biallelicCECR1mutations 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. |
| Databáze: | OpenAIRE |
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