The Genetic Landscape of Diamond-Blackfan Anemia

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.

MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction

“…This, combined with our extensive data from mouse models, indicates that common mechanisms drive disease pathology in MYSM1 deficiency and ribosomopathy syndromes. Interestingly, a homozygous mutation in MYSM1 was recently identified in an exome sequencing study in 1 patient misdiagnosed with DBA (57). Because a significant number of DBA patients do not carry mutations or deletions in established DBA-causing genes (3,8), this together with our current work provides a rationale for screening such patients, as well as patients with other undiagnosed congenital BM failures, for mutations in MYSM1.…”

Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation

“…The patients described in this paper are part of a rare blood disorder cohort that has been studied through the use of WES. WES was performed as previously described (Polfus et al, 2016; Kim et al, 2017; Khajuria et al, 2018; Ulirsch et al, 2018). WES in these cases was performed using genomic DNA obtained from peripheral blood samples of the patients.…”

Deubiquitinase MYSM1 in the Hematopoietic System and beyond: A Current Review

“…Additionally, a sixth patient also carrying the p.E390* MYSM1 mutation in a homozygous state was reported to have neutrophilic panniculitis, as well as reduced B cell count, anemia, and a mild growth retardation [28]. Finally, a novel homozygous mutation p.R478* in MYSM1 was recently identified via whole-exome sequencing in a patient diagnosed with Diamond-Blackfan anemia, a disorder characterized by anemia and to a lesser extent other hematological and developmental abnormalities [29].…”