The Genetic Landscape of Diamond-Blackfan Anemia

Abstract

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.

The nuclear gene rpl18 regulates erythroid maturation via JAK2-STAT3 signaling in zebrafish model of Diamond–Blackfan anemia

“…Ribosomal protein (RP) haploinsufficiency is the major cause of DBA and at least 19 genes that affect ribosomal biogenesis have been found to be linked to DBA 4 . Through whole-exome sequencing in patients in DBA, several rare mutations in previously unreported RP genes were found 4,5 , and one such mutation is a novel nonsynonymous mutation (p.L51S) in rpl18 analysis of pre-rRNA processing in patients' cells showed an increase in the 36S ribosomal subunit compared with controls, indicating a defect in pre-rRNA processing 6 . However, no in vivo, organismal level research has elucidated the function of rpl18 in embryonic development.…”

How I manage children with Diamond‐Blackfan anaemia

“…Within the large variety of endocrine issues in DBA, recent clinical observational studies suggest that women with DBA have an increased incidence of delayed puberty, irregular menstrual cycles and decreased fertility (Lanes et al, 2000;Tufano et al, 2014;Lahoti et al, 2016). It has been demonstrated that pregnancies in DBA are decreased in numbers and more frequently complicated compared to the general population, reflected by a high prevalence of spontaneous abortions (Faivre et al, 2006;Alter et al, 2010).…”

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“…Летальність серед пацієнтів з тяжкими термічними ураженнями залишається високою навіть у спеціалізованих стаціонарах. Особливо високою вона є при критичних (понад 30 % поверхні тіла) та надкритичних (понад 50 %) глибоких опіках [13,22,29].…”

“…Перебіг опікової хвороби залежить від цілої низки факторів: тяжкості опікової травми, віку постраждалого, строків початку лікування, наявності супутніх захворювань. Тяжкість опікової травми визначається, у свою чергу, площею опікових ран та масштабами глибокого пошкодження шкірного покриву [7,24,21,22].…”

“…Пусковим механізмом патологічних змін є морфологічні та функціональні порушення у зоні опікової рани. Відбувається утворення трьох зон опікової рани: первинного некрозу, ішемії й стазу, реактивного набряку [21,22].…”