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Am J Hum Genet. 2018 Dec 6;103(6):930-947. doi: 10.1016/j.ajhg.2018.10.027. Epub 2018 Nov 29.

The Genetic Landscape of Diamond-Blackfan Anemia.

Author information

1
Division of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.
2
Division of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
3
Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
5
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
6
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.
7
Division of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
8
Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01605, USA.
9
Department of Pediatric Hematology/Oncology, Medical University of Warsaw, Warsaw, Poland.
10
Feinstein Institute for Medical Research, Manhasset, NY; Division of Hematology/Oncology and Stem Cell Transplantation, Cohen Children's Medical Center, New Hyde Park, NY; Hofstra Northwell School of Medicine, Hempstead, NY 11030, USA.
11
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 02114, USA.
12
Laboratory of Eukaryotic Molecular Biology, Center for Integrative Biology (CBI), University of Toulouse, CNRS, Toulouse, France.
13
Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia.
14
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
15
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
16
University Paris VII Denis DIDEROT, Faculté de Médecine Xavier Bichat, 75019 Paris, France; Laboratory of Excellence for Red Cell, LABEX GR-Ex, 75015 Paris, France.
17
RNA Therapeutics Institute, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA.
18
Department of Genetics and Genomic Sciences and The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
19
Division of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: sankaran@broadinstitute.org.
20
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: hanna.gazda@childrens.harvard.edu.

Erratum in

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:

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

PMID:
30503522
PMCID:
PMC6288280
[Available on 2019-06-06]
DOI:
10.1016/j.ajhg.2018.10.027
[Indexed for MEDLINE]

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