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The Genetic Landscape of Diamond-Blackfan Anemia.

Authors :
Ulirsch JC
Verboon JM
Kazerounian S
Guo MH
Yuan D
Ludwig LS
Handsaker RE
Abdulhay NJ
Fiorini C
Genovese G
Lim ET
Cheng A
Cummings BB
Chao KR
Beggs AH
Genetti CA
Sieff CA
Newburger PE
Niewiadomska E
Matysiak M
Vlachos A
Lipton JM
Atsidaftos E
Glader B
Narla A
Gleizes PE
O'Donohue MF
Montel-Lehry N
Amor DJ
McCarroll SA
O'Donnell-Luria AH
Gupta N
Gabriel SB
MacArthur DG
Lander ES
Lek M
Da Costa L
Nathan DG
Korostelev AA
Do R
Sankaran VG
Gazda HT
Source :
American journal of human genetics [Am J Hum Genet] 2018 Dec 06; Vol. 103 (6), pp. 930-947. Date of Electronic Publication: 2018 Nov 29.
Publication Year :
2018

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.<br /> (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1537-6605
Volume :
103
Issue :
6
Database :
MEDLINE
Journal :
American journal of human genetics
Publication Type :
Academic Journal
Accession number :
30503522
Full Text :
https://doi.org/10.1016/j.ajhg.2018.10.027