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Ugeskrift For Laeger Oct 2021Hereditary anaemias are the most prevalent genetic disorders worldwide. Until recently, treatment options were mostly supportive or surgical, i.e. splenectomy. Recently,... (Review)
Review
Hereditary anaemias are the most prevalent genetic disorders worldwide. Until recently, treatment options were mostly supportive or surgical, i.e. splenectomy. Recently, several medical treatments designed for frequent haemoglobinopathies such as thalassaemia and sickle cell disease have become available, and numerous new clinical trials hold promise of many more to come. Even rare anaemias such as pyruvate kinase deficiency have promising clinical trials with targeted therapies. Together, these herald hope for future treatment options for patients living with hereditary anaemias, which is discussed in this review.
Topics: Anemia, Hemolytic, Congenital Nonspherocytic; Anemia, Sickle Cell; Hemoglobinopathies; Humans; Splenectomy; Thalassemia
PubMed: 34709160
DOI: No ID Found -
Scandinavian Journal of Clinical and... Dec 2021α-thalassemia is one of the most common monogenic diseases worldwide and is caused by reduced or absent synthesis of α-globin chains, most commonly due to deletions of...
α-thalassemia is one of the most common monogenic diseases worldwide and is caused by reduced or absent synthesis of α-globin chains, most commonly due to deletions of one or more of the α-globin genes. α-thalassemia occurs with high frequency in tropical and subtropical regions of the world and are very rarely found in the indigenous Scandinavian population. Here, we describe four rare forms of α-thalassemia out of which three are novel, found in together 20 patients of Norwegian origin. The study patients were diagnosed during routine hemoglobinopathy evaluation carried out at the Department of Medical Biochemistry, Oslo University Hospital, Norway. The patients were selected for their thalassemic phenotype, despite Norway as country of origin. All samples went through standard hemoglobinopathy evaluation. DNA sequencing and copy number variation (CNV) analysis using quantitative real-time polymerase chain reaction (qPCR) was applied to detect sequence variants and uncommon deletions in the α-globin gene cluster, respectively. Deletion breakpoints were characterized using gap-PCR and DNA sequencing. DNA sequencing revealed a single nucleotide deletion in exon 3 of the gene (NM_000517.4():c.345del) and a novel deletion of 20 nucleotides in exon 2 of the gene (NM_000517.4():c.142_161del). qPCR CNV analysis detected two novel large deletions in the α-globin gene cluster, -(NOR) deletion covering both α-globin genes and (αα)Aurora Borealis affecting the regulatory region, leaving the downstream α-globin genes intact. Even though inherited globin gene disorders are extremely rare in indigenous Scandinavians, the possibility of a carrier state should not be ignored.
Topics: DNA Copy Number Variations; Hemoglobinopathies; Humans; Norway; Real-Time Polymerase Chain Reaction; Sequence Analysis, DNA; alpha-Thalassemia
PubMed: 34791962
DOI: 10.1080/00365513.2021.2004218 -
Clinical Chemistry Sep 2023
Topics: Humans; Hemoglobinopathies
PubMed: 37654066
DOI: 10.1093/clinchem/hvad090 -
Hemoglobin 2016We review and report here the genotypes and phenotypes of 60 novel thalassemia and abnormal hemoglobin (Hb) mutations discovered following the adoption of routine DNA... (Review)
Review
We review and report here the genotypes and phenotypes of 60 novel thalassemia and abnormal hemoglobin (Hb) mutations discovered following the adoption of routine DNA sequencing of both α- and β-globin genes for all UK hemoglobinopathy samples referred for molecular investigation. This screening strategy over the last 10 years has revealed a total of 11 new β chain variants, 15 α chain variants, 19 β-thalassemia (β-thal) mutations and 15 α(+)-thalassemia (α(+)-thal) mutations. The large number of new thalassemia alleles confirms the wide racial heterogeneity of mutations in the UK immigrant population. Eleven of the new variants ran with Hb A on high performance liquid chromatography (HPLC), demonstrating the value of routine sequencing of both α- and β-globin genes for all hemoglobinopathy investigations. The new β chain variants are: Hb Bury [β22(B4)Glu → Asp (HBB: c.69A > T)], Hb Fulwood [β35(C1)Tyr → His (HBB: c.106T > C)], Hb Little Venice [β42(CD1)Phe → Cys (HBB: c.128T > G)], Hb Cork [β57(E1)Asn → Ser (HBB: c.173A > G), Hb Basingstoke [β118(GH1)Phe → Ser (HBB: c.356T > C)], Hb Howden [β20(B2)Val → Ala (HBB: c.62T > C)], Hb Wilton [β41(C7)Phe → Leu (HBB: c.126C > A)], Hb Belsize Park [β120(GH3)Lys → Asn (HBB: c.363A > T)], Hb Hampstead Heath [β2(NA2)His → Gln;β26(B8)Glu → Lys (HBB: c.[6C > G;79G > A])], Hb Grantham [β85(F1)Phe → Cys (HBB: c.257T > G)] and Hb Calgary [β64(E8)Gly → Val (HBB: c.194G > T). The new α chain variants are: Hb Edinburgh [α70(E19)Val → Gly (HBA2: c.212T > G)], Hb Walsgrave [α116(GH4)Glu → Val (HBA2: c.350A > T)], Hb Wexham [α117(GH5) and 118(H1) insertion Ser (HBA1: c.354-355insTCA)], Hb Coombe Park [α127(H10)Lys → Glu (HBA2: c.382A > G)], Hb Oxford [α17(A15)Val → Asp (HBA2: c.53T > A)], Hb Bridlington [α32(B13)Met → Thr (HBA1: c.98T > C), Hb Wolverhampton [α81(F2)Ser → Tyr (HBA2: c.9245C > A)], Hb Little Waltham [α13(A11)Ala → Asp (HBA2: c.41C > A)], Hb Derby [α61(E10)Lys → Arg (HBA1: c.185A > G)], Hb Uttoxter [α74(EF3)Tyr → Asp (HBA2: c.223G > T)], Hb Harehills [α124(H7)Ser → Cys (HBA1: c.374C > G)], Hb Hekinan II [α27(B8)Glu → Asp (HBA1: c.84G > T)], Hb Manitoba IV [α102(G9)Ser → Arg (HBA1: c.307A > C), Hb Witham [α139(HC1)Lys → Arg (HBA2: c.419A > G) and Hb Farnborough [α9(A7)Asn → Asp (HBA1: c.28A > G). In addition, 10 more paralogous α-globin chain variants have been discovered. The novel β-thal alleles are: HBB: c.-138C > G, HBB: c.-121C > T, HBB: c.-80T > G, HBB: c.18_19delTG, HBB: c.219_220insT, HBB: c.315 + 2_315 + 13delTGAGTCTATGGG, HBB: c.316-70C > G, HBB: c.345_346insTGTGCTG, HBB: c.354delC, HBB: c.376-381delCCAGTG, HBB: c.393T > A, HBB: c.394_395insA, HBB: c.375_376insA, HBB: c.*+95_*+107delTGGATTCTinsC, HBB: c.* + 111_*+112delAA, HBB: c.*+112A > T, HBB: c.394C > T, HBB: c.271delG and HBB: c.316-3C > T. The novel α (+ )-thal alleles are: HBA1: c.95+1G > C, HBA1: c.315C > G [Hb Donnington, α104(G11)Cys → Trp], HBA1: c.327delC, HBA1: c.333_345del, HBA1: c.*+96G > A, HBA2: c.2T > G, HBA2: c.112delC, HBA2: c.143delA, HBA2: c.143_146delACCT, HBA2: c.156_157insG, HBA2: c.220_223delGTGG, HBA2: c.305T > C [Hb Bishopstown, α101(G8)Leu → His], HBA2: c.169_170delAA, HBA2: c.1A > T and HBA2: c.-3delA.
Topics: Alleles; Amino Acid Substitution; Genetic Association Studies; Genotype; Hemoglobinopathies; Humans; Mutation; Phenotype; Referral and Consultation; Sequence Analysis, DNA; United Kingdom; alpha-Globins; alpha-Thalassemia; beta-Globins; beta-Thalassemia
PubMed: 26635043
DOI: 10.3109/03630269.2015.1113990 -
American Journal of Hematology Dec 2021We describe presenting features, treatment strategies, and follow-up events involving 41 patients (median age 39 years, range 1-81; 54% males) with high oxygen...
We describe presenting features, treatment strategies, and follow-up events involving 41 patients (median age 39 years, range 1-81; 54% males) with high oxygen affinity (HOA) hemoglobinopathy-associated erythrocytosis, seen at our institution (1973-2020). Thirty-four (83%) patients carried β-chain (13 Malmo, 4 Olympia, 3 San Diego, 2 Wood) and 7 (17%) α-chain (4 Dallas and one each Columbia-Missouri, Jackson, and Wayne) variants. Median (range) hemoglobin (Hgb)/hematocrit (Hct), serum erythropoietin and p50 were 18 g/dL/52.9% (16-21.9/48-66), 10.4 mIU (4-36.3), and 20 mmHg (12-25), respectively. Family history was documented in 24 patients and history of thrombosis in two (5%). Treatment included phlebotomy in 23 and antiplatelet therapy in 21 patients. At a median follow-up of 10 years, 23 (56%) patients reported one or more symptoms that were thought to be related to their increased Hct while thrombosis was documented in 10 (24%) patients. Neither Hgb/Hct level nor active phlebotomy showed a significant correlation with either thrombotic or nonthrombotic symptoms (p > .1 in all instances). Among 23 pregnancies recorded, 78% resulted in live births and no fetal loss was attributed to erythrocytosis. The current study does not implicate Hgb/Hct level as a major contributor of morbidity in HOA hemoglobinopathy-associated erythrocytosis and suggests limited therapeutic value for phlebotomy.
Topics: Adult; Aged; Aged, 80 and over; Child; Disease Management; Female; Hemoglobinopathies; Humans; Infant; Male; Middle Aged; Oxygen; Phlebotomy; Platelet Aggregation Inhibitors; Polycythemia; Retrospective Studies; Young Adult
PubMed: 34633117
DOI: 10.1002/ajh.26375 -
International Journal of Laboratory... Sep 2022Hemoglobinopathies constitute some of the most common inherited disorders worldwide. Manifestations are very severe, patient management is difficult and treatment is not... (Review)
Review
Hemoglobinopathies constitute some of the most common inherited disorders worldwide. Manifestations are very severe, patient management is difficult and treatment is not easily accessible. Preimplantation genetic testing for monogenic disorders (PGT-M) is a valuable reproductive option for hemoglobinopathy carrier-couples as it precludes the initiation of an affected pregnancy. PGT-M is performed on embryos generated by assisted reproductive technologies and only those found to be free of the monogenic disorder are transferred to the uterus. PGT-M has been applied for 30 years now and β-thalassemia is one of the most common indications. PGT may also be applied for human leukocyte antigen typing to identify embryos that are unaffected and also compatible with an affected sibling in need of hemopoietic stem cell transplantation. PGT-M protocols have evolved from PCR amplification-based, where a small number of loci were analysed, to whole genome amplification-based, the latter increasing diagnostic accuracy, enabling the development of more generic strategies and facilitating multiple diagnoses in one embryo. Currently, numerous PGT-M cycles are performed for the simultaneous diagnosis of hemoglobinopathies and screening for chromosomal abnormalities in the embryo in an attempt to further improve success rates and increase deliveries of unaffected babies.
Topics: Embryo Transfer; Female; Genetic Testing; Hemoglobinopathies; Humans; Pregnancy; Preimplantation Diagnosis; beta-Thalassemia
PubMed: 35443077
DOI: 10.1111/ijlh.13851 -
The Lancet. Global Health Jan 2022
Topics: Developing Countries; Hemoglobin, Sickle; Hemoglobinopathies; Humans; Infant, Newborn; Neonatal Screening
PubMed: 34919844
DOI: 10.1016/S2214-109X(21)00559-3 -
Prenatal Diagnosis Dec 1996The inherited haemoglobinopathies are a heterogeneous group of recessive disorders that include the thalassaemias and sickle cell disease. Nearly a thousand mutant... (Review)
Review
The inherited haemoglobinopathies are a heterogeneous group of recessive disorders that include the thalassaemias and sickle cell disease. Nearly a thousand mutant alleles have now been characterized. The mutations are regionally specific and in most cases the geographical and ethnic distributions have been determined providing the foundation for a programme of control through screening, genetic counselling and prenatal diagnosis. The main requirements for methodologies providing molecular diagnosis are speed, cost, convenience and the ability to test for multiple mutations simultaneously. For beta-thalassaemia mutations the procedures that meet these requirements are the amplification refractory mutation system and the reverse dot-blot hybridization system. For alpha-thalassaemia the technique of gap PCR is useful for targeting specific deletion mutations but Southern blotting remains the standard diagnostic test.
Topics: Female; Globins; Hemoglobinopathies; Hemoglobins, Abnormal; Humans; Mutation; Pregnancy; Prenatal Diagnosis; Thalassemia
PubMed: 9061749
DOI: 10.1002/(SICI)1097-0223(199612)16:13<1181::AID-PD93>3.0.CO;2-N -
International Journal of Laboratory... Feb 2023
Topics: Pregnancy; Female; Humans; Prenatal Diagnosis; Hemoglobinopathies
PubMed: 36059158
DOI: 10.1111/ijlh.13960 -
Best Practice & Research. Clinical... Feb 2017The aim of pre-implantation genetic diagnosis (PGD) is to characterize the genetic status of the cells (usually single cells) that have been biopsied from... (Review)
Review
The aim of pre-implantation genetic diagnosis (PGD) is to characterize the genetic status of the cells (usually single cells) that have been biopsied from oocytes/zygotes or embryos created in vitro during assisted reproductive treatment. PGD is a multi-step procedure that requires close collaboration between gynaecologists who are experts in assisted reproduction, embryologists who are experts in micromanipulation of germ cells and in embryo biopsy and geneticists who are experts in genetic analysis at the single-cell level. PGD can be applied as a form of early pre-natal diagnosis with the aim to establish a pregnancy unaffected by a haemoglobinopathy. In addition, PGD can identify embryos that are human leukocyte antigen compatible with an existing sibling affected by a haemoglobinopathy to support a haematopoietic stem cell transplantation. PGD has an advantage over conventional pre-natal diagnosis as it precludes the need to consider terminating an affected ongoing pregnancy. However, PGD is a multi-step, complex and costly procedure with an unpredictable outcome and thus is most suited for couples with an unsuccessful reproductive history or challenging reproductive status. In addition, PGD supports the cure of an affected child. Couples who decide to undergo a PGD cycle should be fully aware of the advantages and limitations. The three teams of health practitioners involved (gynaecologists, embryologists and geneticists) should thoroughly counsel the couples and provide support at all the stages: the initial evaluation of their genetic and reproductive status, all steps of assisted reproduction, embryo biopsy, genetic analysis and, when relevant, follow-up of pregnancy and baby(ies) delivered.
Topics: Biopsy; Embryo Transfer; Female; Fertilization in Vitro; Genetic Testing; HLA Antigens; Hematopoietic Stem Cell Transplantation; Hemoglobinopathies; Humans; Hydrops Fetalis; Pregnancy; Preimplantation Diagnosis; Siblings; Thalassemia; Zygote
PubMed: 27856159
DOI: 10.1016/j.bpobgyn.2016.10.010