blackfan diamond

The ultimate goal of a preimplantation genetic testing and human leukocyte antigen (PGT-HLA) matching programme is the birth of a healthy, HLA-compatible child for the treatment or cure of a sick sibling. Several authors have published successful cases of the births of children HLA-matched to siblings affected by different conditions and diseases. However, there are many reports of failed attempts. Couples seeking an HLA-matched sibling for their affected child look for positive outcomes in the shortest possible time...

Mice with a constitutive increase in p53 activity exhibited features of dyskeratosis congenita (DC), a bone marrow failure syndrome (BMFS) caused by defective telomere maintenance. Further studies confirmed, in humans and mice, that germline mutations affecting TP53 or its regulator MDM4 may cause short telomeres and alter hematopoiesis, but also revealed features of Diamond-Blackfan anemia (DBA) or Fanconi anemia (FA), two BMFSs, respectively, caused by defects in ribosomal function or DNA repair. p53 downregulates several genes mutated in DC, either by binding to promoter sequences ( DKC1 ) or indirectly via the DREAM repressor complex ( RTEL1 , DCLRE1B ), and the p53-DREAM pathway represses 22 additional telomere-related genes...

DNA polymerase epsilon (Pol ε), a component of the core replisome, is involved in DNA replication. Although genetic defects of Pol ε have been reported to cause immunodeficiency syndromes, its role in haematopoiesis remains unknown. Here, we identified compound heterozygous variants (p.[Asp1131fs];[Thr1891del]) in POLE , encoding Pol ε catalytic subunit A (POLE1), in siblings with a syndromic form of severe congenital transfusion-dependent anaemia. In contrast to Diamond-Blackfan anaemia, marked reticulocytopenia or marked erythroid hypoplasia was not found...

Diamond-Blackfan anemia (DBA) is one of the most common inherited causes of bone marrow failure in children. DBA typically presents with isolated erythroid hypoplasia and anemia in infants. Congenital anomalies are seen in 50% of the patients. Over time, many patients experience panhematopoietic defects resulting in immunodeficiency and multilineage hematopoietic cytopenias. Additionally, DBA is associated with increased risk of myelodysplastic syndrome, acute myeloid leukemia and solid organ cancers. As a prototypical ribosomopathy, DBA is caused by heterozygous loss-of-function mutations or deletions in over 20 ribosomal protein genes, with RPS19 being involved in 25% of patients...

p53 is a tumor suppressor, but mouse models revealed that increased p53 activity may cause bone marrow failure, likely through DREAM-mediated gene repression. Here we designed a systematic approach to identify p53-DREAM targets whose repression might contribute to abnormal hematopoiesis. We used gene ontology to analyze transcriptomic changes associated with bone marrow cell differentiation, then ChIP-seq data to identify DREAM-bound promoters. We next created positional frequency matrices to identify evolutionary conserved sequence elements potentially bound by DREAM...

Inherited bone marrow failure syndromes (IBMFSs) include Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, dyskeratosis congenita, severe congenital neutropenia, and other rare entities such as GATA2 deficiency and SAMD9/9L mutations. The IBMFS monogenic disorders were first recognized by their phenotype. Exome sequencing has validated their classification, with clusters of gene mutations affecting DNA damage response (Fanconi anemia), ribosome structure (Diamond-Blackfan anemia), ribosome assembly (Shwachman-Diamond syndrome), or telomere maintenance/stability (dyskeratosis congenita)...

Diamond-Blackfan anemia (DBA) is a congenital hypoplastic anemia characterized by ineffective erythropoiesis. DBA is majorly caused by mutations in the ribosomal protein (RP) genes (Gadhiya and Wills in Diamond-Blackfan Anemia, https://www.statpearls.com/ ; 2023). A suitable disease model that yields a continuous supply of erythroid cells is required to study disease pathogenesis and drug discovery. Toward this, we reprogrammed dermal fibroblasts from a DBA patient with a heterozygous mutation c.22-23delAG in the RPS19 gene identified through exome sequencing...

BACKGROUND: Reaching a precise diagnosis in rare inherited anemia is extremely difficult and challenging, especially in areas with limited use of genetic studies, which makes undiagnosed anemia a unique clinical entity in tertiary hematology centers. In this study, we aim at plotting a stepwise diagnostic approach in children with undiagnosed anemia while identifying indications for genetic testing. PATIENTS AND METHODS: A one-year cross-sectional study involved 44 children and adolescents with undiagnosed anemia after undergoing an initial routine panel of investigations...

The diagnostic work up and surveillance of germline disorders of bone marrow failure and predisposition to myeloid malignancy is complex and involves correlation between clinical findings, laboratory and genetic studies, and bone marrow histopathology. The rarity of these disorders and the overlap of clinical and pathologic features between primary and secondary causes of bone marrow failure, acquired aplastic anemia, and myelodysplastic syndrome may result in diagnostic uncertainty. With an emphasis on the pathologist's perspective, we review diagnostically useful features of germline disorders including Fanconi anemia, Shwachman-Diamond syndrome, telomere biology disorders, severe congenital neutropenia, GATA2 deficiency, SAMD9/SAMD9L diseases, Diamond-Blackfan anemia, and acquired aplastic anemia...

PURPOSE OF REVIEW: Recently, there has been an increasing number of studies on the crosstalk between the bone and the bone marrow and how it pertains to anemia. Here, we discuss four heritable clinical syndromes contrasting those in which anemia affects bone growth and development, with those in which abnormal bone development results in anemia, highlighting the multifaceted interactions between skeletal development and hematopoiesis. RECENT FINDINGS: Anemia results from both inherited and acquired disorders caused by either impaired production or premature destruction of red blood cells or blood loss...

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INTRODUCTION: Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome characterized by erythroid aplasia, physical malformation, and cancer predisposition. Twenty ribosomal protein genes and three non-ribosomal protein genes have been identified associated with DBA. METHODS: To investigate the presence of novel mutations and gain a deeper understanding of the molecular mechanisms of disease, targeted next-generation sequencing was performed in 12 patients with clinically suspected DBA...

The anemias of myelodysplastic syndrome (MDS) and Diamond Blackfan anemia (DBA) are generally macrocytic, always reflect ineffective erythropoiesis, yet result from diverse genetic mutations. To delineate shared mechanisms that lead to cell death, we studied the fate of single erythroid marrow cells from individuals with DBA and MDS-5q. We defined an unhealthy (vs. healthy) differentiation trajectory using transcriptional pseudotime and cell surface proteins. The pseudotime trajectories diverge immediately after cells upregulate transferrin receptor (CD71), import iron, and initiate heme synthesis, although cell death occurs much later...

Pure red cell aplasia (PRCA) is characterized by severe anemia with reticulocytopenia and bone marrow erythroblastopenia. The early erythroblasts are markedly decreased; however, in rare instances, they may be normal or raised in number. There are varied etiologies, namely congenital or acquired and primary or secondary. The congenital PRCA is known as "Diamond-Blackfan anemia." Thymomas, autoimmune disease, lymphomas, infections, and drugs also may be familiar associates. However, the etiologies of PRCA are numerous, and many diseases/infections can be associated with PRCA...

Ribosomal protein (Rp) gene haploinsufficiency can result in Diamond-Blackfan Anemia (DBA), characterized by defective erythropoiesis and skeletal defects. Some mouse Rp mutations recapitulate DBA phenotypes, although others lack erythropoietic or skeletal defects. We generated a conditional knockout mouse to partially delete Rps1 2. Homozygous Rps12 deletion resulted in embryonic lethality. Mice inheriting the Rps12+/- genotype had growth and morphological defects, pancytopenia and impaired erythropoiesis...

Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by congenital anomalies, cancer predisposition and a severe hypo-proliferative anemia. It was the first disease linked to ribosomal dysfunction and >70 % of patients have been identified to have a haploinsufficiency of a ribosomal protein (RP) gene, with RPS19 being the most common mutation. There is significant variability within the disease in terms of phenotype as well as response to therapy suggesting that other genes contribute to the pathophysiology and potential management of this disease...

Ribosomal proteins (Rps) are essential for viability. Genetic mutations affecting Rp genes were first discovered in Drosophila, where they represent a major class of haploinsufficient mutations. One mutant copy gives rise to the dominant "Minute" phenotype, characterized by slow growth and small, thin bristles. Wild-type (WT) and Minute cells compete in mosaics, that is, Rp+/- are preferentially lost when their neighbors are of the wild-type genotype. Many features of Rp gene haploinsufficiency (i.e. Rp+/- phenotypes) are mediated by a transcriptional program...

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure syndrome, usually caused by loss-of function variants in genes encoding ribosomal proteins. The hallmarks of DBA are anemia, congenital anomalies and cancer predisposition. Although DBA usually presents in childhood, the prevalence in later life is increasing due to an expanding repertoire of implicated genes, improvements in genetic diagnosis and increasing life expectancy. Adult patients uniquely suffer the manifestations of end-organ damage caused by the disease and its treatment, and transition to adulthood poses specific issues in disease management...

Systematic studies of germ line genetic predisposition to myeloid neoplasms in adult patients are still limited. In this work, we performed germ line and somatic targeted sequencing in a cohort of adult patients with hypoplastic bone marrow (BM) to study germ line predisposition variants and their clinical correlates. The study population included 402 consecutive adult patients investigated for unexplained cytopenia and reduced age-adjusted BM cellularity. Germ line mutation analysis was performed using a panel of 60 genes, and variants were interpreted per the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines; somatic mutation analysis was performed using a panel of 54 genes...

Diamond-Blackfan anemia is a rare genetic bone marrow failure disorder which is usually caused by mutations in ribosomal protein genes. In the present study, we generated a traceable RPS19-deficient cell model using CRISPR-Cas9 and homology-directed repair to investigate the therapeutic effects of a clinically applicable lentiviral vector at single-cell resolution. We developed a gentle nanostraw delivery platform to edit RPS19 gene in primary human cord blood-derived CD34+ hematopoietic stem and progenitor cells...