RT Journal Article
SR Electronic
T1 The Genetic Landscape of Diamond-Blackfan Anemia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 365890
DO 10.1101/365890
A1 Jacob C. Ulirsch
A1 Jeffrey M. Verboon
A1 Shideh Kazerounian
A1 Michael H. Guo
A1 Daniel Yuan
A1 Leif S. Ludwig
A1 Robert E. Handsaker
A1 Nour J. Abdulhay
A1 Claudia Fiorini
A1 Giulio Genovese
A1 Elaine T. Lim
A1 Aaron Cheng
A1 Beryl B. Cummings
A1 Katherine R. Chao
A1 Alan H. Beggs
A1 Casie A. Genetti
A1 Colin A. Sieff
A1 Peter E. Newburger
A1 Edyta Niewiadomska
A1 Michal Matysiak
A1 Adrianna Vlachos
A1 Jeffrey M. Lipton
A1 Eva Atsidaftos
A1 Bertil Glader
A1 Anupama Narla
A1 Pierre-Emmanuel Gleizes
A1 Marie-Françoise O’Donohue
A1 Nathalie Montel-Lehry
A1 David J. Amor
A1 Steven A. McCarroll
A1 Anne H. O’Donnell-Luria
A1 Namrata Gupta
A1 Stacey B. Gabriel
A1 Daniel G. MacArthur
A1 Eric S. Lander
A1 Monkol Lek
A1 Lydie Da Costa
A1 David. G. Nathan
A1 Andrei K. Korostelev
A1 Ron Do
A1 Vijay G. Sankaran
A1 Hanna T. Gazda
YR 2018
UL http://biorxiv.org/content/early/2018/07/10/365890.abstract
AB 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 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.