TY - JOUR
T1 - The Genetic Landscape of Diamond-Blackfan Anemia
AU - Ulirsch, Jacob C.
AU - Verboon, Jeffrey M.
AU - Kazerounian, Shideh
AU - Guo, Michael H.
AU - Yuan, Daniel
AU - Ludwig, Leif S.
AU - Handsaker, Robert E.
AU - Abdulhay, Nour J.
AU - Fiorini, Claudia
AU - Genovese, Giulio
AU - Lim, Elaine T.
AU - Cheng, Aaron
AU - Cummings, Beryl B.
AU - Chao, Katherine R.
AU - Beggs, Alan H.
AU - Genetti, Casie A.
AU - Sieff, Colin A.
AU - Newburger, Peter E.
AU - Niewiadomska, Edyta
AU - Matysiak, Michal
AU - Vlachos, Adrianna
AU - Lipton, Jeffrey M.
AU - Atsidaftos, Eva
AU - Glader, Bertil
AU - Narla, Anupama
AU - Gleizes, Pierre Emmanuel
AU - O'Donohue, Marie Françoise
AU - Montel-Lehry, Nathalie
AU - Amor, David J.
AU - McCarroll, Steven A.
AU - O'Donnell-Luria, Anne H.
AU - Gupta, Namrata
AU - Gabriel, Stacey B.
AU - MacArthur, Daniel G.
AU - Lander, Eric S.
AU - Lek, Monkol
AU - Da Costa, Lydie
AU - Nathan, David G.
AU - Korostelev, Andrei A.
AU - Do, Ron
AU - Sankaran, Vijay G.
AU - Gazda, Hanna T.
N1 - Publisher Copyright:
© 2018 American Society of Human Genetics
PY - 2018/12/6
Y1 - 2018/12/6
N2 - 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.
AB - 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.
KW - congenital hypoplastic anemia
KW - Diamond-Blackfan anemia
KW - hematopoiesis
KW - human genetics
KW - rare disease
KW - RNA sequencing
KW - whole-exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85058600740&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058600740&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2018.10.027
DO - 10.1016/j.ajhg.2018.10.027
M3 - Article
C2 - 30503522
AN - SCOPUS:85058600740
SN - 0002-9297
VL - 103
SP - 930
EP - 947
JO - American journal of human genetics
JF - American journal of human genetics
IS - 6
ER -