Increased Prevalence of Congenital Heart Disease in Children With Diamond Blackfan Anemia Suggests Unrecognized Diamond Blackfan Anemia as a Cause of Congenital Heart Disease in the General Population

Vlachos, Adrianna; Osorio, Diana S; Atsidaftos, Evangelia; Kang, Jessica; Lababidi, Mohammad Lutfi; Seiden, Howard; Gruber, Dorota; Glader, Bertil; Onel, Kenan; Bodine, David M.; Aspesi, Anna; Dianzani, Irma; Ramenghi, Ugo; Lipton, Jeffrey M.

doi:10.1161/circgenetics.117.002044

Cited by 33 publications

(23 citation statements)

References 5 publications

(7 reference statements)

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“…There is growing evidence that RP mutations can be found in patients with very mild or absent hematologic manifestations, as previously described, for instance, in a family with no sign of DBA where a truncating germline mutation in RPS20 cosegregated with colon cancer (Nieminen et al., ). This is also supported by the recent report of two unrelated patients with congenital heart disease and mutations in RPS24 who were not anemic (Vlachos et al., ). Our observation that VUS reported in population databases could be involved in DBA pathogenesis highlights the need to deepen our knowledge about the possible presence in the general population of silent carriers of RP mutations and atypical cases of DBA.…”

Section: Discussionsupporting

confidence: 69%

A functional assay for the clinical annotation of genetic variants of uncertain significance in Diamond-Blackfan anemia

et al. 2018

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Diamond–Blackfan anemia (DBA) is a rare genetic hypoplasia of erythroid progenitors characterized by mild to severe anemia and associated with congenital malformations. Clinical manifestations in DBA patients are quite variable and genetic testing has become a critical factor in establishing a diagnosis of DBA. The majority of DBA cases are due to heterozygous loss‐of‐function mutations in ribosomal protein (RP) genes. Causative mutations are fairly straightforward to identify in the case of large deletions and frameshift and nonsense mutations found early in a protein coding sequence, but diagnosis becomes more challenging in the case of missense mutations and small in‐frame indels. Our group recently characterized the phenotype of lymphoblastoid cell lines established from DBA patients with pathogenic lesions in RPS19 and observed that defective pre‐rRNA processing, a hallmark of the disease, was rescued by lentiviral vectors expressing wild‐type RPS19. Here, we use this complementation assay to determine whether RPS19 variants of unknown significance are capable of rescuing pre‐rRNA processing defects in these lymphoblastoid cells as a means of assessing the effects of these sequence changes on the function of the RPS19 protein. This approach will be useful in differentiating pathogenic mutations from benign polymorphisms in identifying causative genes in DBA patients.

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Section: Discussionsupporting

confidence: 69%

A functional assay for the clinical annotation of genetic variants of uncertain significance in Diamond-Blackfan anemia

et al. 2018

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“… 48 , 50 , 51 , 65 Damaging human variants in ribosomal subunits RPS19, RPL5, 4 and RPL35A have been identified in patients with CHD 4 (PCGC consortium data not shown) and also contribute to Diamond-Blackfan anemia, 50 , 66 , 67 a disorder that is accompanied by CHD in 30% of patients. 68 …”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency

Ward

Tai

Morton

et al. 2021

Circulation Research

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Rationale: NAA15 is a component of the N-terminal (Nt) acetyltransferase complex, NatA. The mechanism by which NAA15 haploinsufficiency causes congenital heart disease (CHD) remains unknown. To better understand molecular processes by which NAA15 haploinsufficiency perturbs cardiac development, we introduced NAA15 variants into human induced pluripotent stem cells (iPSCs) and assessed the consequences of these mutations on RNA and protein expression. Objective: We aim to understand the role of NAA15 haploinsufficiency in cardiac development by investigating proteomic effects on NatA complex activity, and identifying proteins dependent upon a full amount of NAA15. Methods and Results: We introduced heterozygous LoF, compound heterozygous and missense residues (R276W) in iPS cells using CRISPR/Cas9. Haploinsufficient NAA15 iPS cells differentiate into cardiomyocytes, unlike NAA15-null iPS cells, presumably due to altered composition of NatA. Mass spectrometry (MS) analyses reveal ~80% of identified iPS cell NatA targeted proteins displayed partial or complete Nt-acetylation. Between null and haploinsufficient NAA15 cells Nt-acetylation levels of 32 and 9 NatA-specific targeted proteins were reduced, respectively. Similar acetylation loss in few proteins occurred in NAA15 R276W iPSCs. In addition, steady-state protein levels of 562 proteins were altered in both null and haploinsufficient NAA15 cells; eighteen were ribosomal-associated proteins. At least four proteins were encoded by genes known to cause autosomal dominant CHD. Conclusions: These studies define a set of human proteins that requires a full NAA15 complement for normal synthesis and development. A 50% reduction in the amount of NAA15 alters levels of at least 562 proteins and Nt-acetylation of only 9 proteins. One or more modulated proteins are likely responsible for NAA15-haploinsufficiency mediated CHD. Additionally, genetically engineered iPS cells provide a platform for evaluating the consequences of amino acid sequence variants of unknown significance on NAA15 function.

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“…The DBA Registry of North America (DBAR), a database of more than 700 patients, was established in 1991 and provides important information regarding the epidemiology and biology of DBA 8 – 12 . Almost half of patients exhibit physical abnormalities, except short stature, which is a known feature of DBA but could also be a result of chronic anemia, iron overload, corticosteroid administration, or a combination of all three.…”

Section: Clinical Featuresmentioning

confidence: 99%

An update on the pathogenesis and diagnosis of Diamond–Blackfan anemia

2018

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Diamond–Blackfan anemia (DBA) is a rare congenital hypoplastic anemia characterized by a block in erythropoiesis at the progenitor stage, although the exact stage at which this occurs remains to be fully defined. DBA presents primarily during infancy with macrocytic anemia and reticulocytopenia with 50% of cases associated with a variety of congenital malformations. DBA is most frequently due to a sporadic mutation (55%) in genes encoding several different ribosomal proteins, although there are many cases where there is a family history of the disease with varying phenotypes. The erythroid tropism of the disease is still a matter of debate for a disease related to a defect in global ribosome biogenesis. Assessment of biological features in conjunction with genetic testing has increased the accuracy of the diagnosis of DBA. However, in certain cases, it continues to be difficult to firmly establish a diagnosis. This review will focus on the diagnosis of DBA along with a description of new advances in our understanding of the pathophysiology and treatment recommendations for DBA.

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Increased Prevalence of Congenital Heart Disease in Children With Diamond Blackfan Anemia Suggests Unrecognized Diamond Blackfan Anemia as a Cause of Congenital Heart Disease in the General Population

Cited by 33 publications

References 5 publications

A functional assay for the clinical annotation of genetic variants of uncertain significance in Diamond-Blackfan anemia

A functional assay for the clinical annotation of genetic variants of uncertain significance in Diamond-Blackfan anemia

Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency

An update on the pathogenesis and diagnosis of Diamond–Blackfan anemia

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