Aim: In this article, we present two cases of severe fetal hemolytic anemia based on a beta-thalassaemia trait inherited from a single parent.
Results: These cases, presented at 20 and 28 weeks' gestation, necessitated intra-uterine blood transfusions. This occurrence is remarkable because it challenges the common assumption that beta-thalassaemia typically has no prenatal implications regarding fetal anemia.
It is well known that modifiers play a role in ameliorating or exacerbating disease phenotypes in patients and carriers of recessively inherited disorders such as sickle cell disease and thalassemia. Here, we give an overview of the literature concerning a recently described association in carriers of Loss-of-Function variants with a beta-thalassemia-like phenotype including the characteristic elevated levels of HbA. That acts as modifier in beta-thalassemia carriers became evident from three reported cases in whom combined heterozygosity of and gene variants was observed to resemble a mild beta-thalassemia intermedia phenotype.
View Article and Find Full Text PDFBackground: Hemoglobinopathies, the most common inherited blood disorder, are frequently underdiagnosed. Early identification of carriers is important for genetic counseling of couples at risk. The aim of this study was to develop and validate a novel machine learning model on a multicenter data set, covering a wide spectrum of hemoglobinopathies based on routine complete blood count (CBC) testing.
View Article and Find Full Text PDFSeveral types of haemoglobinopathies are caused by copy number variants (CNVs). While diagnosis is often based on haematological and biochemical parameters, a definitive diagnosis requires molecular DNA analysis. In some cases, the molecular characterisation of large deletions/duplications is challenging and inconclusive and often requires the use of specific diagnostic procedures, such as multiplex ligation-dependent probe amplification (MLPA).
View Article and Find Full Text PDFHemoglobinopathies are the most common monogenic disorders in the world with an ever increasing global disease burden each year. As most hemoglobinopathies show recessive inheritance carriers are usually clinically silent. Programmes for preconception and antenatal carrier screening, with the option of prenatal diagnosis are considered beneficial in many endemic countries.
View Article and Find Full Text PDFThe prevalence of hemoglobinopathies in The Netherlands is increasing due to migration. Hemoglobinopathies are severe hereditary diseases. An informed reproductive choice by at-risk couples, such as pre-implantation diagnosis or termination of affected pregnancies, can be made if carriers are detected prior to conception.
View Article and Find Full Text PDFAs in most Northern European countries, the prevalence of hemoglobinopathies in The Netherlands is increasing due to migration. Although hemoglobinopathies are severe chronic diseases with few treatment options, timely detection of carriers allows at-risk couples to make informed reproductive choices such as pre-implantation diagnosis, prenatal diagnosis or termination of affected pregnancies. Using a quantitative design, we evaluated the prevalence of hemoglobinopathies in The Hague region, The Netherlands.
View Article and Find Full Text PDFWe describe a first Dutch case of Hb M Saskatoon (HBB:c.190C > T p.His64Tyr) in a 47-year-old female Dutch patient who presented with cyanosis, hemolysis, and abnormal co-oximetry.
View Article and Find Full Text PDFThroughout the past decades, the search for a treatment for severe hemoglobinopathies has gained increased interest within the scientific community. The discovery that ɤ-globin expression from intact alleles complements defective alleles underlying β-thalassemia and sickle cell disease, has provided a promising opening for research directed at relieving ɤ-globin repression mechanisms and, thereby, improve clinical outcomes for patients. Various gene editing strategies aim to reverse the fetal-to-adult hemoglobin switch to up-regulate ɤ-globin expression through disabling either repressor genes or repressor binding sites in the promoter regions.
View Article and Find Full Text PDFAccurate and consistent interpretation of sequence variants is integral to the delivery of safe and reliable diagnostic genetic services. To standardize the interpretation process, in 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published a joint guideline based on a set of shared standards for the classification of variants in Mendelian diseases. The generality of these standards and their subjective interpretation between laboratories has prompted efforts to reduce discordance of variant classifications, with a focus on the expert specification of the ACMG/AMP guidelines for individual genes or diseases.
View Article and Find Full Text PDFDuring the last few years, next-generation sequencing (NGS) has undergone a rapid transition from a research setting to a clinical application, becoming the method of choice in many clinical genetics laboratories for the detection of disease-causing variants in a variety of genetic diseases involving multiple genes. The hemoglobinopathies are the most frequently found Mendelian inherited monogenic disease worldwide and are composed of a complex group of disorders frequently involving the inheritance of more than one abnormal gene. This review aims to present the role of NGS in both screening and pre- and post-natal diagnostics of the hemoglobinopathies, and the added value of NGS is discussed based on the results described in the literature.
View Article and Find Full Text PDFIntroduction: The high-sequence homology of the α-globin-gene cluster is responsible for microhomology-mediated recombination events during meiosis, resulting in a high density of deletion breakpoints within a 10 kb region. Commonly used deletion detection methods, such as multiplex ligation-dependent probe amplification (MLPA) and Southern blot, cannot exactly define the breakpoints. This typically requires long-range PCR, which is not always successful.
View Article and Find Full Text PDFObjectives: Artifactually altered glycated hemoglobin (HbA) concentrations are frequently linked to hemoglobin (Hb) variants. Their expression and detection require in-depth analysis.
Methods: Cation exchange high performance liquid chromatography (HPLC) (Bio-Rad Variant™ II; Trinity Biotech Premier Hb9210 Resolution), capillary electrophoresis (CE) (Sebia Capillarys 2 Flex Piercing) and mass spectrometry (MS) (Waters) were used for variant detection; Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA) and next generation sequencing (NGS) were used for DNA analysis; HbA was measured with cation exchange HPLC (Bio-Rad Variant™ II; Arkray Adams HA-8180V; Tosoh HLC-723 G7), CE (Sebia Capillarys 2 Flex Piercing), boronate affinity HPLC (Trinity Biotech Hb9210 Premier), immunoassay (Cobas c501 Tina-quant HbA Gen.
Unstable hemoglobinopathies (UHs) are rare anemia disorders (RADs) characterized by abnormal hemoglobin (Hb) variants with decreased stability. UHs are therefore easily precipitating, causing hemolysis and, in some cases, leading to dominant beta-thalassemia (dBTHAL). The clinical picture of UHs is highly heterogeneous, inheritance pattern is dominant, instead of recessive as in more prevalent major Hb syndromes, and may occur .
View Article and Find Full Text PDFIntroduction: The accurate measurement of HbA is essential for the detection of β-thalassaemia carriers and as no single calibrant is used by the various manufacturers of analysers, differences are seen in results obtained. The World Health Organization International Reference Reagent for HbA (WHO IRR 89/666) was made available to diagnostic laboratories in the 1980s and remains the only international reference material available. A previous study (2015) demonstrated that the WHO IRR remained suitable for use as an HbA standard as tested by 52 participants in the UK NEQAS Haematology Abnormal Haemoglobins Programme.
View Article and Find Full Text PDFBackground: Standardization of laboratory tests can be a long process, and this is the case with regards to the methods used to measure hemoglobin A (HbA), an important marker for beta-thalassemia and other thalassemic conditions. The IFCC standardization project started in 2004, and it took at least 15 years before developing a reference measurement procedure, defining and producing calibrators and certified reference materials.
Methods: A series of steps have to be undertaken in order to promote the standardization in the field, a process involving a number of stakeholders (manufacturers, scientific societies, national health bodies, laboratory professionals, clinicians).
A woman completely lacking Hb A on the high performance liquid chromatography (HPLC) analysis, presented with a novel deletional (εγ)δβ-thal and a δ-globin gene variant. This combination causes a β-thalassemia (β-thal) minor phenotype. The woman was referred by a hematologist due to abnormal blood counts.
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