Familial genotypic and phenotypic heterogeneity and its implications on genetic counseling exemplified in two cases of hereditary pyropoikilocytosis/erythrocytic spectrin‐linked hemolytic anemia masquerading as congenital dyserythropoietic anemia

2021 ◽  
Author(s):  
Manu Jamwal ◽  
Anu Aggarwal ◽  
Prashant Sharma ◽  
Deepak Bansal ◽  
Amita Trehan ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Hemolytic Anemia ◽  
Phenotypic Heterogeneity ◽  
Congenital Dyserythropoietic Anemia

Congenital dyserythropoietic anemia type 1 with a novel mutation in the CDAN1 gene previously diagnosed as congenital hemolytic anemia

2013 ◽  
Vol 97 (5) ◽  
pp. 650-653 ◽  
Author(s):  
Hisanori Fujino ◽  
Sayoko Doisaki ◽  
Young-Dong Park ◽  
Asahito Hama ◽  
Hideki Muramatsu ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Novel Mutation ◽  
Congenital Dyserythropoietic Anemia ◽  
Congenital Hemolytic Anemia

scholarly journals Novel PKLR missense mutation (A300P) causing pyruvate kinase deficiency in an Omani Kindred - PK deficiency masquerading as Congenital Dyserythropoietic Anemia.

2021 ◽  
Author(s):  
Naglaa Fawaz ◽  
Ismail Beshlawi ◽  
Alauldeen Alqasim ◽  
Mathew Zachariah ◽  
Roberta Russo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Missense Mutation ◽  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Novel Mutation ◽  
Chronic Anemia ◽  
Pyruvate Kinase Deficiency ◽  
Congenital Dyserythropoietic Anemia ◽  
Laboratory Features

A 15 year child is presented with transfusion dependent chronic anemia. The clinical and laboratory features suggested a chronic nonspherocytic hemolytic anemia (CNSHA) with bone marrow suggestive of congenital dyserythropoietic anemia (CDA). DNA studies revealed the underlying novel mutation in the PKLR gene responsible for pyruvate kinase deficiency.

scholarly journals Use of Next Generation Sequencing Panel for Routine Diagnosis of Hereditary Hemolytic Anemias

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2325-2325 ◽  
Author(s):  
Archana M Agarwal ◽  
Jay L Patel ◽  
Adam Clayton ◽  
Noel Scott Reading
Keyword(s):  
Genetic Counseling ◽  
Next Generation Sequencing ◽  
Hemolytic Anemia ◽  
Erythroid Cell ◽  
Red Cell ◽  
Next Generation ◽  
Novel Mutations ◽  
Ugt1a1 Gene ◽  
Rbc Membrane ◽  
Generation Sequencing

Abstract Hereditary hemolytic anemia (HHA) are a heterogeneous group of disorders due to germline mutations of the red cell cytoskeleton (e.g. hereditary spherocytosis (HS) and hereditary elliptocytosis/pyropoikilocytosis (HE/HPP)) or enzyme deficiencies (e.g. glucose 6 phosphate dehydrogenase deficiency (G6PD) and pyruvate kinase deficiency (PKD). Routine morphological and biochemical analysis may be inconclusive in neonates due to the physiological nature of erythroid cell maturation and can also be misleading in transfusion-dependent patients. Additionally, there has been increasing awareness of inherited red cell membrane disorders that are not easily identified by routine laboratory approaches. For example, clinically insignificant defects of RBC membrane genes (e.g. alpha LELY and alpha LEPRA in SPTA1), which can be present in the parents without significant hemolysis, may result in compound heterozygosity in the offspring, causing severe morbidity or even mortality due to significant hemolysis. Awareness of these low expression alleles is important for genetic counseling purposes. Molecular studies, although becoming more mainstream, have not been used extensively to diagnose these disorders. This is most likely due to the complex genetic nature of these disorders (e.g. large genes with multiple exons involved, and multi-gene disorders (i.e. hyperbilirubinemia due to HS as well as involvement of genes involved in bilirubin metabolism). The accessibility of next generation sequencing (NGS) methods in the clinical laboratory has made diagnosing complex genetic disorders feasible. Our current diagnostic panel includes 28 genes encoding cytoskeletal proteins and enzymes, and covers the complete coding region, splice site junctions, and, where appropriate, deep intronic or regulatory regions. Targeted gene capture and library construction for NGS are performed using a Sure Select kit (Agilent). Indexed samples are quantified using qPCR and then pooled prior to sequencing on the Illumina NextSeq or HiSeq instruments. Samples are sequenced using 150 bp paired-end sequencing. This panel includes genes responsible for RBC membrane defects, enzyme deficiencies, as well as bilirubin uridine diphosphate glucuronosyltransferase (UGT1A) genes that have a distinct role in hyperbilirubinemia. We now report the first 268 patients evaluated using our NGS panel between 2015-2018. These patients were evaluated using an Institutional Review Board Protocol (IRB - 00077285). The age of the patients ranged from newborn to 68 years. These patients presented with symptoms ranging from mild lifelong anemia to severe hemolytic anemia with extreme hyperbilirubinemia. Genetic variants were classified according to the American College of Medical Genetics (ACMG) guidelines. We identified pathogenic and likely pathogenic variants in 64/268 (24%) patients that were clearly responsible for the disease phenotype (e.g. moderate to severe hemolytic anemia). Approximately half of them were novel mutations. Moreover, 29/268 (11%) of patients were homozygous for a promoter polymorphism in the UGT1A1 gene A(TA)7TAA (UGT1A1*28), which may lead to reduced expression of the UGT1A1 gene and Gilbert's syndrome. Furthermore, 4/29 UGT1A1 polymorphism cases were associated with pathogenic spectrin mutations, likely increasing the severity of the clinical phenotype in these patients. Overall, the most commonly mutated genes were SPTB and SPTA1, encoding spectrin subunits, followed by PKLR and ANK1 (Table 1). Complex interactions between variants in the SPTA1 gene and the common alpha-LELY and alpha-LEPRA alleles were predicted to be associated with HPP and autosomal recessive HS in 12/64 patients. Furthermore, 23/268 (9%) patients had mutations that were predicted to cause moderate to severe anemia if inherited with another mutation, making them important for genetic counseling purposes (data not shown). Our results demonstrate that many patients with hemolytic anemia harbor complex combinations of known and novel mutations in RBC cytoskeleton/enzyme genes. Many variants of unknown significance were also identified that could potentially contribute to disease. To conclude, the use of NGS provides a cost-effective and comprehensive method to assist in the diagnosis of hemolytic anemias, especially in instances where complex gene-gene interactions are suspected. Disclosures No relevant conflicts of interest to declare.

Whole-exome analysis to detect congenital hemolytic anemia mimicking congenital dyserythropoietic anemia

2018 ◽  
Vol 108 (3) ◽  
pp. 306-311 ◽  
Author(s):  
Motoharu Hamada ◽  
Sayoko Doisaki ◽  
Yusuke Okuno ◽  
Hideki Muramatsu ◽  
Asahito Hama ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Congenital Dyserythropoietic Anemia ◽  
Whole Exome ◽  
Exome Analysis ◽  
Congenital Hemolytic Anemia

scholarly journals Peroxiredoxin II (PRDX2) Is a Novel Candidate Gene for Congenital Dyserythropoietic Anemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3605-3605 ◽  
Author(s):  
Myesa Emberesh ◽  
Katie Giger Seu ◽  
Sana Emberesh ◽  
Lisa Trump ◽  
Mary Risinger ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Candidate Gene ◽  
Hemolytic Anemia ◽  
Peripheral Blood ◽  
Intracellular Signaling ◽  
Cellular Proliferation ◽  
Conflicts Of Interest ◽  
Congenital Dyserythropoietic Anemia ◽  
Immune Hemolytic Anemia

Abstract CDAR (ClinicalTrials.gov Identifier: NCT02964494), a registry for patients with Congenital Dyserythropoietic Anemia (CDA) in North America, has been created with the goal to provide a longitudinal database and associated biorepository to facilitate natural history studies and research on the molecular pathways involved in the pathogenesis of CDAs. A 1 y.o. female patient with non-immune hemolytic anemia with suboptimal reticulocytosis, requiring frequent transfusions, and with the pathologic diagnosis of CDA was enrolled in CDAR. Her father had a similar phenotypical presentation in early childhood and underwent splenectomy at 3 years of age. Since then, he has rarely required transfusions but he continues to have a mild anemia at baseline with characteristics of hemolysis and with suboptimal reticulocytosis; at the time of enrollment, he had hemoglobin of 9.3 g/dL with absolute reticulocyte count of 115 x 106 cells/µl. Next Generation sequencing and deletion/duplication assay for the known CDA-associated genes (CDAN1, C15ORF41, SEC23B, KIF23, GATA1) identified no mutations. Whole-exome sequencing for the patient and her parents (family-trio design) revealed a novel PRDX2 missense variant (c.154C>T; p.Pro52Ser) present in heterozygous state in both proband and her father; no mutation in this gene was present in the asymptomatic mother. In silico prediction programs suggest that this variant is probably damaging and deleterious, causing a non-conservative substitution of a phylogenetically highly-conserved amino acid (down to Baker's yeast), and located in an enzymatically active protein domain, adjacent to the active Cys51, with the potential to change its conformation. Peroxiredoxin II is highly expressed during terminal erythropoiesis and is one of the most abundant proteins after hemoglobin in erythroblasts and mature erythrocytes. It is an antioxidant enzyme that reduces the reactive oxygen species (ROS), like hydrogen peroxide and alkyl hydroperoxides readily produced within the erythroid cells due to the presence of heme iron and oxygen. In addition, PRDX2 has been implicated in intracellular signaling, cellular proliferation and differentiation, and as a regulator of iron homeostasis. PRDX2-/- mice were found to have hemolytic anemia with evidence of oxidative damage of the erythrocyte proteins resulting to decreased red blood cell (RBC) survival. The aim of this work is to validate the pathogenetic role of the PRDX2 variant found in this family as the molecular cause of this dominantly-inherited CDA and further investigate the role of PRDX2 in human terminal erythropoiesis. Central review of the patient's bone marrow aspirate and biopsy slides, according to the CDAR protocol, revealed erythroid hyperplasia with dyserythropoiesis, including megaloblastoid changes, nuclear lobation and fragmentation, and binucleated erythroblasts (less than 10%), compatible with atypical CDA. There were rare erythroids with cytoplasmic bridging but no nuclear bridges. Review of the peripheral blood smear showed significant poikilocytosis, mild polychromasia, and the presence of blister and ghost cells reminiscent of G6PD deficiency, pointing to RBC damage by oxidative stress. Induced pluripotent stem cells (iPSCs) and EBV-immortalized lymphocytes were generated from the patients' peripheral blood mononuclear cells after informed consent per CDAR protocol, to allow further in vitro studies of the peroxiredoxin II-deficiency. Flow cytometry confirmed significantly increased ROS in the patients' derived versus control EBV-immortalized lymphocytes as well as in the reticulocytes and mature erythrocytes of the proband and her father, indicating that their PRDX2 variant is causing loss-of-function of the enzyme and increased oxidative stress. Further work is ongoing to explore the mechanisms of pathogenicity of peroxiredoxin II deficiency towards human dyserythropoiesis and decreased erythrocyte lifespan. To our knowledge, this is the first case of anemia described in humans associated with PRDX2 mutation implicating this gene as a novel candidate gene for atypical, dominantly-inherited CDA. Disclosures No relevant conflicts of interest to declare.

Autoimmune hemolytic anemia

1975 ◽  
Vol 135 (10) ◽  
pp. 1293-1300 ◽  
Author(s):  
J. V. Dacie
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia

Letter: Heinz body hemolytic anemia

1976 ◽  
Vol 136 (9) ◽  
pp. 1067a-1067
Author(s):  
E. P. Gabor
Keyword(s):  
Hemolytic Anemia ◽  
Heinz Body
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