Beta-thalassemia is characterized by a reduced production of hemoglobin A (HbA, alpha-2/beta-2), which results from the reduced synthesis of beta-globin chains relative to alpha-globin chains, thus causing an imbalance in globin chain production and hence abnormal erythropoiesis. The ... Beta-thalassemia is characterized by a reduced production of hemoglobin A (HbA, alpha-2/beta-2), which results from the reduced synthesis of beta-globin chains relative to alpha-globin chains, thus causing an imbalance in globin chain production and hence abnormal erythropoiesis. The disorder is clinically heterogeneous (summary by Ottolenghi et al., 1975). Absence of beta globin causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. For clinical purposes, beta-thalassemia is divided into thalassemia major (transfusion dependent), thalassemia intermedia (of intermediate severity), and thalassemia minor (asymptomatic, carrier state). The molecular and clinical aspects of the beta-thalassemias were reviewed by Olivieri (1999). The remarkable phenotypic diversity of the beta-thalassemias reflects the heterogeneity of mutations at the HBB locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors (Weatherall, 2001).
By means of a simplified method for trophoblast biopsy together with restriction endonuclease analysis of fetal DNA, Old et al. (1982) made first-trimester prenatal diagnosis in the case of 3 fetuses at risk ... - Prenatal Diagnosis By means of a simplified method for trophoblast biopsy together with restriction endonuclease analysis of fetal DNA, Old et al. (1982) made first-trimester prenatal diagnosis in the case of 3 fetuses at risk for hemoglobinopathy: 2 at risk for homozygous beta-thalassemia and 1 at risk for sickle cell anemia. Saiki et al. (1988) devised a simple and rapid nonradioactive method for detecting genetic variation and applied it to the diagnosis of sickle cell anemia and beta-thalassemia. The procedure involved the selective amplification of a segment of the human beta-globin gene with oligonucleotide primers and a thermostable DNA polymerase, followed by hybridization of the amplified DNA with allele-specific oligonucleotide probes covalently labeled with horseradish peroxidase. The hybridized probes were detected with a simple colorimetric assay. In Sardinia, Rosatelli et al. (1985) used the synthetic oligonucleotide method for prenatal detection of the beta-zero-39 (nonsense) mutation type of beta-thalassemia. In a mouse model for beta-thalassemia, Holding and Monk (1989) were able to make the diagnosis in single blastomeres removed from embryos of 4 to 8 cells by PCR amplification. Monk and Holding (1990) demonstrated reproducible amplification of a 680-basepair sequence within the human beta-globin gene from individual human oocytes and the first polar bodies isolated from them. They used restriction enzyme digestion of the amplified DNA to confirm the identity of the fragment. The authors proposed that analysis of the DNA from the first polar body will facilitate preimplantation diagnosis of sickle cell anemia. Ding et al. (2004) described a method for noninvasive prenatal diagnosis by analysis of circulating nucleic acids. Circulating fetal-specific DNA sequences have been detected and constitute a fraction of the total DNA in maternal plasma. The robust discrimination of single-nucleotide differences between circulating DNA species is technically challenging and demanded the adoption of highly sensitive and specific analytical systems. Ding et al. (2004) developed a method based on single-allele base extension reaction and mass spectrometry which allowed for the reliable detection of fetal-specific alleles, including point mutations and SNPs, in maternal plasma. The approach was applied to exclude the fetal inheritance of the 4 most common Southeast Asian beta-thalassemia mutations in at-risk pregnancies between weeks 7 and 21 of gestation: 41/42delCTTT (141900.0326), IVS2 654C-T (141900.0368), -28A-G (141900.0381), and 17A-T (141900.0311). Fetal genotypes were correctly predicted in all cases studied. Fetal haplotype analysis based on a SNP linked to the HBB gene in maternal plasma also was achieved.
Patients with thalassemia major present in the first year of life with severe anemia; they are unable to maintain a hemoglobin level about 5 gm/dl. Clinical details of this disorder have been detailed extensively in numerous monographs and ... Patients with thalassemia major present in the first year of life with severe anemia; they are unable to maintain a hemoglobin level about 5 gm/dl. Clinical details of this disorder have been detailed extensively in numerous monographs and were summarized by Weatherall et al. (1995). Modell et al. (2000) found that about 50% of UK patients with beta-thalassemia major die before the age of 35 years, mainly because conventional iron-chelation therapy is too burdensome for full adherence. Cao and Galanello (2010) reviewed the clinical features of the 3 forms of beta-thalassemia. Affected infants with thalassemia major fail to thrive and become progressively pale. Feeding problems, diarrhea, irritability, recurrent bouts of fever, and enlargement of the abdomen, caused by splenomegaly, may occur. If an adequate transfusion program is followed, growth and development are normal until age 10 to 11 years. Afterwards, affected individuals are at risk of developing severe complications related to posttransfusional iron overload, depending on their compliance with chelation therapy. Patients with thalassemia intermedia show a markedly heterogeneous clinical picture. The principal symptoms are pallor, jaundice, cholelithiasis, liver and spleen enlargement, moderate to severe skeletal changes, leg ulcers, extramedullary masses of hyperplastic erythroid marrow, a tendency to develop osteopenia and osteoporosis, and thrombotic complications resulting from a hypercoagulable state because of the lipid membrane composition of the abnormal red blood cells (particularly in splenectomized patients). Transfusions are usually not required. Iron overload occurs mainly from increased intestinal absorption of iron caused by ineffective erythropoiesis. Carriers of beta-thalassemia are clinically asymptomatic. Cao and Galanello (2010) also reviewed the hematologic findings in the 3 forms. Patients with thalassemia major have a severe microcytic and hypochromic anemia, associated with increased number of red blood cells and low mean corpuscular volume (MCV) and mean corpuscular Hb (MCH). Peripheral blood smear shows, in addition to microcytosis and hypochromia, anisocytosis, poikilocytosis (spiculated tear drop and elongated cells), and nucleated red blood cells (i.e., erythroblasts). The number of erythroblasts is related to the degree of anemia and is markedly increased after splenectomy. Patients with thalassemia intermedia have a moderate anemia and show a markedly heterogeneous hematologic picture, ranging in severity from that of the beta-thalassemia carrier state to that of thalassemia major. The characteristic hematologic features in carriers are microcytosis (reduced red blood cell volume), hypochromia (reduced red blood cell Hb content), increased HbA2 level (the minor component of the adult Hb, alpha2delta2), and unbalanced alpha/nonalpha globin chain synthesis. However, several environmental or genetic factors may modify this phenotype, leading either to thalassemia intermedia, despite the presence of a single beta-globin gene affected, or to hematologically atypical carrier state. Some atypical beta-thalassemia heterozygotes have either normal red cell indices or normal HbA2 level, or both, with a completely silent hematologic phenotype. This condition is detected only by the imbalanced alpha-nonalpha globin chain synthesis and is referred to as silent beta-thalassemia (Cao and Moi, 2000). Wainscoat et al. (1983) showed that coinheritance of alpha-thalassemia with homozygous beta-thalassemia resulted in amelioration of the beta-thalassemia. Kulozik et al. (1987) showed that heterozygous beta-thalassemia was associated with unusually severe clinical manifestations when coinherited with an extra alpha-globin gene; in each of 5 cases 1 chromosome 16 carried 3 alpha-globin genes. Camaschella et al. (1987) found the same aggravation of the clinical picture with triplicated alpha locus. This is a particularly instructive example of gene interaction. To gain insight into the cellular and structural alterations of thalassemic bone, Mahachoklertwattana et al. (2003) studied bone histomorphometry and biochemical and hormonal profiles in children and adolescents with suboptimally treated beta-thalassemia disease. Seventeen patients underwent iliac crest bone biopsy for histomorphometric analyses. Most patients had growth retardation and delayed bone age. Bone mineral density (BMD) was low especially at the lumbar spine. Serum IGF1 (147440) levels were almost always low. Bone histomorphometry revealed increased osteoid thickness, osteoid maturation time, and mineralization lag time, which indicate impaired bone matrix maturation and defective mineralization. In addition, iron deposits appeared along mineralization fronts and osteoid surfaces. The authors concluded that delayed bone maturation and focal osteomalacia are the pathogenesis of bone disease in suboptimally blood-transfused thalassemics with iron overload. They suggested that iron deposits in bone and low circulating IGF1 levels may partly contribute to the above findings. Premawardhena et al. (2005) studied 109 Sri Lankan hemoglobin E beta-thalassemia patients over 5 years. They found that 25 patients were not receiving transfusion, and transfusion was discontinued in an additional 37 patients without deleterious effect. Premawardhena et al. (2005) identified several genetic and environmental factors that may contribute to the phenotypic diversity of the disorder, including modifiers of hemoglobin F (see 142250) production, malaria (see 611162), and age-related changes in adaptive function. They proposed that hemoglobin E beta-thalassemia can be managed without transfusion in many patients and that age-related changes in the adaptation to anemia indicate that more cost-effective management approaches should be explored. O'Donnell et al. (2009) studied Sri Lankan patients with HbE beta-thalassemia for exposure to malaria caused by Plasmodium falciparum or P. vivax. They found that there were high frequencies of antibodies to both malaria parasites, as well as DNA-based evidence of current infection with P. vivax. Comparisons with age-matched controls showed that there was a higher frequency of antibodies in thalassemic patients, particularly against P. vivax and in young children, that was unlikely to be related to transfusion. A higher frequency was also found in patients who had undergone splenectomy. O'Donnell et al. (2009) proposed that patients with HbE beta-thalassemia may be more prone to malaria, particularly P. vivax malaria.
For a review of mutations in the HBB gene and the beta-globin gene cluster causing beta-thalassemia, see 141900.
Uda et al. (2008) found that the C allele of dbSNP rs11886868 in the BCL11A gene (606557) was ... For a review of mutations in the HBB gene and the beta-globin gene cluster causing beta-thalassemia, see 141900. Uda et al. (2008) found that the C allele of dbSNP rs11886868 in the BCL11A gene (606557) was associated with an ameliorated phenotype in patients with beta-thalassemia due to increased production of fetal hemoglobin.
Beta-thalassemia is one of the most common autosomal recessive disorders worldwide. It is highly prevalent in populations in the Mediterranean, Middle East, Transcaucasus, Central Asia, Indian subcontinent, and Far East. It is also relatively common in populations of ... Beta-thalassemia is one of the most common autosomal recessive disorders worldwide. It is highly prevalent in populations in the Mediterranean, Middle East, Transcaucasus, Central Asia, Indian subcontinent, and Far East. It is also relatively common in populations of African descent. The highest incidences are reported in Cyprus (14%), Sardinia (12%), and Southeast Asia (Cao and Galanello, 2010). In Lebanon, beta-thalassemia is the predominant genetic defect. Makhoul et al. (2005) investigated the religious and geographic distribution of beta-thalassemia mutations in Lebanon and traced their origins. Sunni Muslims had the highest beta-thalassemia carrier rate and presented the greatest heterogeneity, with 16 different mutations. Shiite Muslims followed closely with 13 mutations, whereas Maronites represented 11.9% of all beta-thalassemic subjects and carried 7 different mutations. RFLP haplotype analysis showed that the observed genetic diversity originated from both new mutational events and gene flow from population migration. The estimated number of worldwide annual births of patients with beta-thalassemia major is 22,989; for beta-E-thalassemia, 19,128; and for S-beta thalassemia, 11,074 (Modell and Darlison, 2008 and Weatherall, 2010).
Thalassemia major is suspected in an infant or child younger than age two years with severe microcytic anemia, mild jaundice, and hepatosplenomegaly. Untreated, affected children usually manifest failure to thrive and expansion of the bone marrow to compensate for ineffective erythropoiesis. ...
Clinical DiagnosisThalassemia major is suspected in an infant or child younger than age two years with severe microcytic anemia, mild jaundice, and hepatosplenomegaly. Untreated, affected children usually manifest failure to thrive and expansion of the bone marrow to compensate for ineffective erythropoiesis. Thalassemia intermedia is suspected in individuals who present at a later age with similar but milder clinical findings. Individuals with thalassemia intermedia only rarely require treatment with blood transfusion. TestingHematologic Testing Red blood cell indices show microcytic anemia (Table 1).Table 1. Red Blood Cell Indices in Beta-ThalassemiaView in own windowRed Blood Cell IndexNormal 1 AffectedCarrier 1 MaleFemaleβ-Thal Majorβ-Thal MinorMean corpuscular volume (MCV fl)
89.1±5.0187.6±5.550-70 <79 Mean corpuscular hemoglobin (MCH pg)30.9±1.930.2±2.112-20<27 Hemoglobin (Hb g/dL)15.9±1.014.0±0.9<7Males: 11.5-15.3 Females: 9.1-141. Data from Galanello et al Peripheral blood smear Affected individuals demonstrate the red blood cell (RBC) morphologic changes of microcytosis, hypochromia, anisocytosis, poikilocytosis (spiculated tear-drop and elongated cells), and nucleated red blood cells (i.e., erythroblasts). The number of erythroblasts is related to the degree of anemia and is markedly increased following splenectomy. Carriers demonstrate reduced mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) (Table 1), and RBC morphologic changes that are less severe than in affected individuals. Erythroblasts are normally not seen. Qualitative and quantitative hemoglobin analysis (by cellulose acetate electrophoresis and DE-52 microchromatography or HPLC) identifies the amount and type of hemoglobin present. The following hemoglobin (Hb) types are most relevant to β-thalassemia: Hemoglobin A (HbA): two globin alpha chains and two globin beta chains (α2 β2) Hemoglobin F (HbF): two globin alpha chains and two globin gamma chains (α2 γ2) Hemoglobin A2 (HbA2): two globin alpha chains and two globin delta chains α2 δ2) The hemoglobin pattern in β-thalassemia varies by β-thalassemia type (Table 2).Table 2. Hemoglobin Patterns in Beta-Thalassemia (Age >12 Months)View in own windowHemoglobin TypeNormal 1 AffectedCarrierβº-Thal Homozygotes 2 β+-Thal Homozygotes or β+/βº Compound Heterozygotes 3 β-Thal MinorHbA96%-98%010%-30%92%-95%HbF<1%95%-98%70%-90%0.5%-4%HbA2 2%-3%2%-5%2%-5%>3.5%1. Data from Telen & Kaufman 2. βº-thalassemia: complete absence of globin beta chain production3. β+-thalassemia: variable degree of reduction of globin beta chain synthesisHemoglobin electrophoresis and HPLC also detect other hemoglobinopathies (S, C, E, OArab, Lepore) that may interact with β-thalassemia. Bone marrow examination is usually not necessary for diagnosis of affected individuals. The bone marrow is extremely cellular, mainly as a result of marked erythroid hyperplasia, with a myeloid/erythroid ratio reversed from the normal (3 or 4) to 0.1 or less. In vitro synthesis of radioactive labeled globin chains in affected individuals reveals the following βº-thalassemia: a complete absence of globin beta chains and a marked excess of globin alpha chains compared with globin gamma chains. The α/γ ratio is greater than 2.0. β+-thalassemia: a variable degree of reduction of globin beta chains resulting in severe (thalassemia major) to mild (thalassemia intermedia) clinical phenotypes. The imbalance of the α/β and γ ratio is similar to that in βº-thalassemia major. Molecular Genetic TestingGene. HBB is the only gene in which mutations are known to cause β-thalassemia (see Differential Diagnosis). Clinical testing The β-thalassemias can be caused by more than 200 different HBB mutations [Huisman et al 1997, globin.cse.psu.edu]; however, the prevalent molecular defects are limited in each at-risk population (see Table 4). This phenomenon has greatly facilitated molecular genetic testing. The principal molecular genetic testing used in beta-thalassemia is summarized in Table 3. Table 3. Summary of Molecular Genetic Testing Used in Beta-ThalassemiaView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityHBBTargeted mutation analysis Mutation panels vary by laboratoryVariable depending on mutations included in panel and individual's ethnicityClinical Sequence analysisSequence variants 2 99%Deletion / duplication analysis 3Deletion of HBB or beta-globin gene clusterVariable depending on individual's ethnicity 1. The ability of the test method used to detect a mutation that is present in the indicated gene 2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. Typically, sequencing involves coding region and flanking intronic regions; mutations in the non-coding region and heterozygous deletions of an exon(s) or other gene region are not detected by this analysis.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyConfirmation of the diagnosis of beta-thalassemia in a proband requires identification of the disease-causing mutations in HBB. The appropriate order for molecular genetic testing: 1.Targeted mutation analysis 2.Sequence analysis3.Deletion/duplication analysis Prognostication. Distinguishing thalassemia major from thalassemia intermedia at the molecular level for the purpose of prognostication requires defining of the HBB mutations and evaluating for coinheritance of those genetic determinants able to sustain a continuous production of gamma globin chains (HbF) in adulthood or able to reduce the alpha/non-alpha globin chain imbalance, such as alpha-thalassemia (see Genotype-Phenotype Correlations). Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersOther phenotypes associated with mutations in HBB are sickle cell disease caused by A>T substitution at codon 6 (p.Glu6Val) (c.17A>T, NM_000518.4) and other nucleotide substitutions responsible for hemoglobin variants (globin.cse.psu.edu).
The phenotypes of the homozygous β-thalassemias include thalassemia major and thalassemia intermedia. The clinical severity of the β-thalassemia syndromes depends on the extent of alpha globin chain/non-alpha globin chain (i.e., β+ γ) imbalance. The non-assembled alpha globin chains that result from unbalanced alpha globin chain/non-alpha globin chain synthesis precipitate in the form of inclusions. These alpha globin chain inclusions damage the erythroid precursors in the bone marrow and in the spleen, causing ineffective erythropoiesis. Individuals with thalassemia major usually come to medical attention within the first two years of life; they subsequently require regular red blood cell transfusions to survive. Those who present later and rarely require transfusion are said to have thalassemia intermedia....
The phenotypes of the homozygous β-thalassemias include thalassemia major and thalassemia intermedia. The clinical severity of the β-thalassemia syndromes depends on the extent of alpha globin chain/non-alpha globin chain (i.e., β+ γ) imbalance. The non-assembled alpha globin chains that result from unbalanced alpha globin chain/non-alpha globin chain synthesis precipitate in the form of inclusions. These alpha globin chain inclusions damage the erythroid precursors in the bone marrow and in the spleen, causing ineffective erythropoiesis. Individuals with thalassemia major usually come to medical attention within the first two years of life; they subsequently require regular red blood cell transfusions to survive. Those who present later and rarely require transfusion are said to have thalassemia intermedia.β-thalassemia major. Clinical presentation of thalassemia major occurs between ages six and 24 months. Affected infants fail to thrive and become progressively pale. Feeding problems, diarrhea, irritability, recurrent bouts of fever, and progressive enlargement of the abdomen caused by splenomegaly may occur. If the diagnosis of thalassemia major is established at this stage and if a regular transfusion program that maintains a minimum Hb concentration of 95 to 105 g/L is initiated, growth and development are normal until age ten to 11 years. After age ten to 11 years, affected individuals are at risk of developing severe complications related to iron overload, depending on their compliance with chelation therapy (see Management). Complications of iron overload in children include growth retardation and failure of sexual maturation and in adults include involvement of the heart (dilated cardiomyopathy), liver (fibrosis and cirrhosis), and endocrine glands (resulting in diabetes mellitus and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands). In individuals who have been regularly transfused, iron overload results mainly from transfusions. Other complications are hypersplenism, chronic hepatitis (resulting from infection with the viruses that cause hepatitis B and/or hepatitis C), cirrhosis (from iron overload and chronic hepatitis), HIV infection, venous thrombosis, and osteoporosis. The risk for hepatocellular carcinoma is increased secondary to liver viral infection, iron overload, and longer survival [Borgna-Pignatti et al 2004].At present, prognosis for individuals who have been well transfused and treated with appropriate chelation is open-ended. Myocardial disease caused by transfusional siderosis is the most important life-limiting complication of iron overload in β-thalassemia. In fact, cardiac complications are reported to cause 71% of the deaths in individuals with β-thalassemia major [Borgna-Pignatti et al 2004]. The classic clinical picture of thalassemia major is presently only seen in some developing countries, in which the resources for carrying out long-term transfusion programs are not available. The most relevant features of untreated or poorly transfused individuals are growth retardation, pallor, jaundice, brown pigmentation of the skin, poor musculature, genu valgum, hepatosplenomegaly, leg ulcers, development of masses from extramedullary hematopoiesis, and skeletal changes that result from expansion of the bone marrow. These skeletal changes include deformities of the long bones of the legs and typical craniofacial changes (bossing of the skull, prominent malar eminence, depression of the bridge of the nose, tendency to a mongoloid slant of the eye, and hypertrophy of the maxillae, which tends to expose the upper teeth), and osteoporosis. Individuals who have not been regularly transfused usually die before the third decade. Individuals who have been poorly transfused are also at risk for complications of iron overload.β-thalassemia intermedia. Clinical features are pallor, jaundice, cholelithiasis, liver and spleen enlargement, moderate to severe skeletal changes, leg ulcers, extramedullary masses of hyperplastic erythroid marrow, a tendency to develop osteopenia and osteoporosis, and thrombotic complications resulting from iron accumulation and hypercoagulable state secondary to the lipid membrane composition of the abnormal red blood cells [Eldor & Rachmilewitz 2002. Cappellini et al 2012]. By definition, transfusions are not required or only occasionally required. Iron overload occurs mainly from increased intestinal absorption of iron caused by deficiency of hepcidin, a 25-amino acid peptide produced by hepatocytes that plays a central role in the regulation of iron homeostasis [Nemeth & Ganz 2006, Origa et al 2007].The associated complications of iron overload present later, but may be as severe as those seen in individuals with thalassemia major who depend on transfusions.
Any inherited or acquired condition that reduces the alpha/non-alpha globin chain imbalance in β-thalassemia results in a lesser degree of alpha globin chain precipitation and leads to a mild β-thalassemia phenotype ...
Any inherited or acquired condition that reduces the alpha/non-alpha globin chain imbalance in β-thalassemia results in a lesser degree of alpha globin chain precipitation and leads to a mild β-thalassemia phenotype One of the most common and consistent mechanisms is homozygosity or compound heterozygosity for two β+-thalassemia mild and silent mutations (see Table 5).In contrast, compound heterozygosity for a mild/silent β+ and a severe mutation produces a variable phenotype, ranging from thalassemia intermedia to thalassemia major. Therefore, the presence of this genotype does not predict a mild phenotype. Hemoglobin E (HbE), which is a thalassemic structural variant, characterized by the presence of an abnormal structure as well as biosynthetic defect, should be included in this group. The nucleotide substitution at codon 26, producing the HbE variant (α2 β226 E>K), activates a potential cryptic RNA splice region, resulting in alternative splicing at this position. The homozygous state for HbE results in a mild hemolytic microcytic anemia. Compound heterozygosity for β-thalassemia and HbE results in a wide range of often severe but sometimes mild or even clinically asymptomatic clinical phenotypes.The clinical picture resulting from homozygosity for β+-thalassemia or homozygosity for βº-thalassemia mutations may be ameliorated by coinheritance of mutations in the gene encoding the alpha globin chain associated with α-thalassemia, which reduces the output of the genes encoding the alpha globin chains and therefore decreases the alpha/non-alpha globin chain imbalance. Because coinherited α-thalassemia does not always produce a consistent effect, it cannot be used to predict phenotype. The coinheritance of some genetic determinants able to sustain a continuous production of gamma globin chains (HbF) in adult life may also reduce the extent of alpha/non-alpha globin chain imbalance:The β-thalassemia mutation per se increases the gamma globin chain (HbF) output. This occurs in the following two situations: δβº-thalassemia is caused by deletions of variable size in the HBB gene cluster. Deletions remove only the 5' region of the HBB promoter, which also results in high levels of HbA2. Co-transmission of hereditary persistence of fetal hemoglobin (HPFH), which is the result of single point mutations of the hemoglobin Gγ (HBG2) or hemoglobin Aγ (HBG1) gene promoter. The most common is a single-base substitution C to T at position 158 upstream of the transcription start site of the HBG2 gene, which is silent in normal individuals and in β-thalassemia heterozygotes, but leads to increased HbF production in individuals with erythropoietic stress, as occurs in homozygous β thalassemia. This HBG2 mutation, sometimes referred to as Gγ-158 C>T, is officially designated c.-210C>T. It is in linkage disequilibrium (in cis configuration) with some HBB mutations (see Table 4 and Table 5). This explains the mild phenotype that may result from the inheritance of these mutations. Coinheritance of heterocellular HPFH may or may not be linked to the HBB gene cluster. Recent studies using genome-wide association studies (G-WAS) have identified two quantitative trait loci (QTLs) (Bcl11A on chromosome 2p16 and HBS1L-MYB intergenic region on chromosome 6q23) that account for 20%-30% of the common variation in HbF levels in healthy adults and persons with beta–thalassemia and sickle cell disease [Uda et al 2008, Thein et al 2009]. Bcl11A seems to be involved in the regulation of the globin gene switching process [Sankaran et al 2008]. The ameliorating effect of QTLs and α-thalassemia on the phenotypic severity of homozygous beta°-thalassemia has recently been reported [Galanello et al 2009]. Recently, an additional potential locus has been identified when point mutations in KLF1 were found to be associated with HPFH in a Maltese family and in a family from Sardinia [Borg et al 2010, Satta et al 2011]. KLF1 is a zinc-finger erythroid transcriptional regulator that binds to the critical promoter elements of the adult β-globin gene. It plays a critical role in regulating the switch between fetal and adult hemoglobin expression both by direct activation of β-globin and indirect repression of γ-globin gene expression in adult erythroid progenitors via regulation of BCL11A. Recently, several KLF1 mutations have been identified in individuals with a thalassemia carrier phenotype and a particularly mild form of sickle cell disease [Gallienne et al 2012]. It is likely that many other HbF-associated QTLs also exist. Other modifying factors. The clinical phenotype of homozygous β-thalassemia may also be modified by the coinheritance of other genetic factors mapping outside the β-globin gene cluster. The best known of these modifying genes is UGT1A, the gene encoding uridin-diphosphoglucuronyltransferase. When combined with thalassemia major or thalassemia intermedia, the UGT1A mutation causing Gilbert disease (i.e., (TA)7 configuration instead of the (TA)6 in the TATA box) leads to increased jaundice and increased risk of gallstones [Origa et al 2009]. Less defined modifying factors are genes coding for HFE-associated hereditary hemochromatosis and genes involved in bone metabolism. In some instances, heterozygous β-thalassemia may lead to the phenotype of thalassemia intermedia instead of the asymptomatic carrier state. Known molecular mechanisms include the following: Heterozygosity for mutations in HBB that result in hyper-unstable hemoglobins (dominant β-thalassemia), which precipitate in the red cell membrane together with unassembled alpha globin chains, resulting in markedly ineffective erythropoiesis. Most of these HBB mutations lie in the third exon and lead to the production of a markedly unstable Hb variant often not detectable in peripheral blood. Compound heterozygosity for typical β-thalassemia mutations and the triple or (less frequently) quadruple alpha gene arrangement (αα/αα or ααα/ααα or αααα/αα may increase the imbalance in the ratio of alpha/non- alpha globin chains. Duplications of the entire alpha globin gene cluster have been reported as causing thalassemia intermedia in association with the β-thalassemia carrier state [Harteveld et al 2008, Sollaino et al 2009]
β-thalassemia associated with other features. In rare instances the β-thalassemia defect does not lie in HBB or in the β-globin gene cluster. In instances in which the β-thalassemia trait is associated with other features, the molecular lesion has been found either in the gene encoding the transcription factor TFIIH (β-thalassemia trait associated with xeroderma pigmentosum and tricothiodystrophy) or in the X-linked transcription factor GATA-1 (X-linked thrombocytopenia with thalassemia) (see GATA1-Related Cytopenia) [Viprakasit et al 2001, Freson et al 2002]. ...
β-thalassemia associated with other features. In rare instances the β-thalassemia defect does not lie in HBB or in the β-globin gene cluster. In instances in which the β-thalassemia trait is associated with other features, the molecular lesion has been found either in the gene encoding the transcription factor TFIIH (β-thalassemia trait associated with xeroderma pigmentosum and tricothiodystrophy) or in the X-linked transcription factor GATA-1 (X-linked thrombocytopenia with thalassemia) (see GATA1-Related Cytopenia) [Viprakasit et al 2001, Freson et al 2002]. Few conditions share similarities with homozygous β-thalassemia. The very rare, so-called dominant β-thalassemias or thalassemic hemoglobinopathies result in an abnormal hyper-unstable protein product. The presence of hyper-unstable hemoglobin should be suspected in any individual with thalassemia intermedia when both parents are hematologically normal or in families with a pattern of autosomal dominant transmission of the thalassemia intermedia phenotype. HBB sequencing establishes the diagnosis. The genetically determined sideroblastic anemias are easily differentiated because of ring sideroblasts in the bone marrow and variably elevated serum concentration of erythrocyte protoporphyrin. Most sideroblastic anemia is associated with defects in the heme biosynthetic pathway, especially δ-aminolevulinic acid synthase (see also X-Linked Sideroblastic Anemia and Ataxia). Congenital dyserythropoietic anemias do not have high HbF and do have other distinctive features, such as multinuclearity of the red blood cell precursors. A few acquired conditions associated with high HbF (juvenile chronic myeloid leukemia, aplastic anemia) may be mistaken for β-thalassemia, even though they have very characteristic hematologic features. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Beta-thalassemia majorBeta-thalassemia intermediaBeta-thalassemia minor
The initial step following diagnosis of β-thalassemia in an individual is to distinguish thalassemia intermedia from thalassemia major (see Testing Strategy). The diagnosis of thalassemia major implies the need for a regular transfusion program; the diagnosis of thalassemia intermedia implies the need for intermittent transfusions on an as-needed basis....
Evaluations Following Initial DiagnosisThe initial step following diagnosis of β-thalassemia in an individual is to distinguish thalassemia intermedia from thalassemia major (see Testing Strategy). The diagnosis of thalassemia major implies the need for a regular transfusion program; the diagnosis of thalassemia intermedia implies the need for intermittent transfusions on an as-needed basis.Treatment of ManifestationsA comprehensive review of the management of thalassemia major and thalassemia intermedia has been published by Thalassemia International Federation [Cappellini et al 2008] and is available at the TIF Web site (see www.thalassaemia.org.cy).Thalassemia major. Regular transfusions correct the anemia, suppress erythropoiesis, and inhibit increased gastrointestinal absorption of iron. Before starting the transfusions, it is absolutely necessary to carry out hepatitis B vaccination and perform extensive red blood cell antigen typing, including Rh, Kell, Kidd, and Duffy and serum immunoglobulin determination — the latter of which detects individuals with IgA deficiency who need special (repeatedly washed) blood unit preparation before each transfusion. The transfusion regimen is designed to obtain a pre-transfusion Hb concentration of 95-100 g/L. Transfusions are usually given every two to three weeks. Thalassemia intermedia. Treatment of individuals with thalassemia intermedia is symptomatic and based on splenectomy and folic acid supplementation. Treatment of extramedullary erythropoietic masses is based on radiotherapy, transfusions, or, in selected cases, hydroxyurea (with a protocol similar to that used for sickle cell disease). Hydroxyurea also increases globin gamma chains and may have other undefined mechanisms. Because individuals with thalassemia intermedia may develop iron overload from increased gastrointestinal absorption of iron or from occasional transfusions, chelation therapy is started when the serum ferritin concentration exceeds 300 µg/L [Origa et al 2007]. Bone marrow transplantation Bone marrow transplantation (BMT) from an HLA-identical sib represents an alternative to traditional transfusion and chelation therapy. If BMT is successful, iron overload may be reduced by repeated phlebotomy, thus eliminating the need for iron chelation. The outcome of BMT is related to the pretransplantation clinical conditions, specifically the presence of hepatomegaly, extent of liver fibrosis, and magnitude of iron accumulation. In children who lack the above risk factors, disease-free survival is over 90%. Adults with beta-thalassemia are at a higher risk for transplant-related toxicity due to an advanced phase of the disease and have a cure rate of 65% with current treatment protocol [Isgrò et al 2010]. Chronic graft-versus-host disease (GVHD) of variable severity may occur in 5%-8% of individuals. BMT from unrelated donors has been carried out on a limited number of individuals with β-thalassemia. Provided that selection of the donor is based on stringent criteria of HLA compatibility and that individuals have limited iron overload, results are comparable to those obtained when the donor is a compatible sib [La Nasa et al 2005]. However, because of the limited number of individuals enrolled, further studies are needed to confirm these preliminary findings. Affected individuals without matched donors could also benefit from haploidentical mother-to-child transplantation, the results of which appear encouraging [Sodani et al 2011].Cord blood transplantation. Cord blood transplantation from a related donor offers a good probability of a successful cure and is associated with a low risk for graft versus host disease (GVHD) [Pinto & Roberts 2008]. For couples who have already had a child with thalassemia and who undertake prenatal diagnosis in a subsequent pregnancy, prenatal identification of HLA compatibility between the affected child and an unaffected fetus allows collection of placental blood at delivery and the option of cord blood transplantation to cure the affected child [Orofino et al 2003]. On the other hand, in case of an affected fetus and a previous unaffected child, the couple may decide to continue the pregnancy and pursue BMT later, using the unaffected child as the donor. Unrelated cord blood transplantation has been explored as an alternative option for affected individuals without a suitable HLA matched unrelated adult donor. However, this strategy may be limited by less than adequate cell dose and higher rates of primary graft failure. One potential strategy may be the use of two cord blood units in order to achieve the desired cell dose, as has been done in individuals with malignancy. However, this approach may be associated with a higher rate of acute GVHD, which may add to the burden of morbidity and mortality for this population. For these reasons, unrelated cord blood transplantation seems to be a suboptimal strategy for individuals with thalassemia [Ruggeri et al 2011].Prevention of Primary ManifestationsEarly detection of anemia, the primary manifestation of the disease, allows early appropriate treatment and monitoring.Prevention of Secondary ComplicationsTransfusional iron overload. The most common secondary complications are those related to transfusional iron overload, which can be prevented by adequate iron chelation. After ten to 12 transfusions, chelation therapy is initiated with desferrioxamine B (DFO) administered five to seven days a week by 12-hour continuous subcutaneous infusion via a portable pump. Recommended dosage depends on the individual's age and the serum ferritin concentration. Young children start with 20-30 mg/kg/day, increasing up to 40 mg/kg/day after age five to six years. The maximum dose is 50 mg/kg/day after growth is completed. The dose may be reduced if serum ferritin concentration is low. By maintaining the total body iron stores below critical values (i.e., hepatic iron concentration <7.0 mg per gram of dry weight liver tissue), desferrioxamine B therapy prevents the secondary effects of iron overload, resulting in a consistent decrease in morbidity and mortality [Borgna-Pignatti et al 2004]. Ascorbate repletion (daily dose not to exceed 100-150 mg) increases the amount of iron removed after DFO administration. Side effects of DFO chelation therapy are more common in the presence of relatively low iron burden and include ocular and auditory toxicity, growth retardation, and, rarely, renal impairment and interstitial pneumonitis. DFO administration also increases susceptibility to Yersinia infections. The major drawback of DFO chelation therapy is low compliance resulting from complications of administration.In clinical practice, the effectiveness of DFO chelation therapy is monitored by routine determination of serum ferritin concentration. However, serum ferritin concentration is not always reliable for evaluating iron burden because it is influenced by other factors, the most important being the extent of liver damage. Determination of liver iron concentration in a liver biopsy specimen shows a high correlation with total body iron accumulation and is the gold standard for evaluation of iron overload. However, (1) liver biopsy is an invasive technique involving the possibility (though low) of complications; (2) liver iron content can be affected by hepatic fibrosis, which commonly occurs in individuals with iron overload and HCV infection; and (3) irregular iron distribution in the liver can lead to possible false-negative results [Clark et al 2003]. In recent years, MRI techniques for assessing iron loading in the liver and heart have improved [Pennell 2005, Wood 2008]. T2 and T2* parameters have been validated for liver iron concentration. Cardiac T2* is reproducible, is applicable between different scanners, correlates with cardiac function, and relates to tissue iron concentration [Pennell 2005, Wood 2008]. Clinical utility of T2* in monitoring individuals with siderotic cardiomyopathy has been demonstrated. In a recent study, twelve human hearts from transfusion-dependent affected individuals after either death or transplantation for end-stage heart failure underwent cardiovascular magnetic resonance R2* (the reciprocal of T2*) measurement. Tissue iron concentration was measured in multiple samples of each heart with inductively coupled plasma atomic emission spectroscopy, providing calibration in humans for cardiovascular magnetic resonance R2* against myocardial iron concentration and detailing the iron distribution throughout the heart in iron overload [Carpenter et al 2011].Magnetic biosusceptometry (SQUID), which gives a reliable measurement of hepatic iron concentration, is another option [Fischer et al 2003]; however, magnetic susceptometry is presently available only in a limited number of centers worldwide.Two other chelators have been introduced into clinical use: deferiprone and deferasirox.Deferiprone (L-1), a bidentated oral chelator, available for several years in many countries, is administered in a dose of 75-100 mg/kg/day. The main side effects of deferiprone therapy include neutropenia, agranulocytosis, arthropathy, and gastrointestinal symptoms [Galanello & Campus 2009] that demand close monitoring. The effect of deferiprone on liver iron concentration may vary among the individuals treated. However, results from independent studies suggest that deferiprone may be more cardioprotective than desferrioxamine; compared to those being treated with DFO, individuals being treated with deferiprone have better myocardial MRI pattern and less probability of developing (or worsening pre-existing) cardiac disease [Anderson et al 2002, Piga et al 2003]. These retrospective observations have been confirmed in a prospective study [Pennell et al 2006]. After many years of controversy, deferiprone is emerging as a useful iron chelator equivalent/alternative to desferrioxamine.Deferasirox recently became available for clinical use in patients with thalassemia. It is effective in adults and children and has a defined safety profile that is clinically manageable with appropriate monitoring. The most common treatment-related adverse events are gastrointestinal disorders, skin rash, and a mild, non-progressive increase in serum creatinine concentration [Cappellini 2008]. Post-marketing experience and several phase IV studies will further evaluate the safety and efficacy of deferasirox. New strategies of chelation using a combination of desferrioxamine and deferiprone have been effective in individuals with severe iron overload. Retrospective, prospective, and randomized clinical studies have shown that combined iron chelation with deferiprone and desferrioxamine rapidly reduces myocardial siderosis, improves cardiac and endocrine function, reduces liver iron and serum ferritin concentration, reduces cardiac mortality, and improves survival; toxicity is manageable [Tanner et al 2007, Galanello et al 2010]. Cardiac disease. In the past few years, particular attention has been directed to the early diagnosis and treatment of cardiac disease because of its critical role in determining the prognosis of individuals with β-thalassemia. Assessment of myocardial siderosis and monitoring of cardiac function combined with intensification of iron chelation can result in excellent long-term prognoses [Wood 2008, Kirk et al 2009, Chouliaras et al 2011]. Osteoporosis. Osteoporosis is a common complication in adults with thalassemia major or thalassemia intermedia [Voskaridou & Terpos 2008]. Its origin is multifactorial, making it difficult to manage. Treatment involves appropriate hormonal replacement, an effective regimen of transfusion and iron chelation, calcium and vitamin D administration, and regular physical activity. Specific treatment with bisphosphonates has been attempted with promising results in several studies and confirmed in a randomized trial [Voskaridou et al 2008]. However, since the origin of bone disease in thalassemia major is multifactorial and some of the underlying pathogenic mechanisms are still unclear, further research in this field is needed to allow for the design of optimal therapeutic measures [Skordis & Toumba 2011].SurveillanceFor individuals with thalassemia major, follow up to monitor the effectiveness of transfusion therapy and chelation therapy and their side effects includes the following: Monthly physical examination by a physician familiar with the affected individual and the disease Every two months: assessment of liver function tests (serum concentration of ALT) Every three months: determination of serum ferritin concentration Every six months during childhood: assessment of growth and developmentAnnual Ophthalmologic and audiologic examinations Complete cardiac evaluation, and evaluation of thyroid, endocrine pancreas, parathyroid, adrenal, and pituitary function Liver ultrasound evaluation and determination of serum alpha-fetoprotein concentration in adults with hepatitis C and iron overload for early detection of hepatocarcinoma Bone densitometry to assess for osteoporosis in the adult Regular gallbladder echography for early detection of cholelithiasis [Origa et al 2009], particularly in individuals with the Gilbert syndrome genotype (i.e., presence of the (TA)7/(TA)7 motif in the UGT1A promoter)Agents/Circumstances to AvoidThe following should be avoided: Alcohol consumption, which in individuals with liver disease has a synergistic effect with iron-induced liver damage Iron-containing preparations Evaluation of Relatives at RiskIf prenatal diagnosis has not been performed and if the disease-causing mutations have been identified in an affected family member, it is appropriate to offer molecular genetic testing to at-risk sibs to allow early diagnosis and appropriate treatment. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Provided that a multidisciplinary team is available, pregnancy is possible and safe, and usually has a favorable outcome in women with thalassemia. An increasing number of women with thalassemia major and thalassemia intermedia may, therefore, have children. Although hypogonadotropic hypogonadism remains a common condition in thalassemia major, gonadal function is usually intact and fertility is usually retrievable. Pregnancy also appears to be safe in most women with thalassemia intermedia, although larger and more detailed studies are needed. Indeed, an increased risk for certain complications cannot yet be excluded. For example, women with thalassemia intermedia who had never previously received a blood transfusion or who had received a minimal quantity of blood are reported to be at risk for severe alloimmune anemia if blood transfusions are required during pregnancy [Origa et al 2010]. Therapies Under Investigation New chelation strategies are under investigation. A recent metabolic iron balance study in six affected individuals wherein the relative effectiveness of deferasirox (30 mg/kg/day) and deferoxamine (40 mg/kg/day) was compared, alone and in combination, has demonstrated a negative iron balance in 5/6 using the combination of drugs just three days a week [Grady et al 2013]. Moreover, preliminary studies using in combination the two oral chelators deferasirox and deferiprone appear to be encouraging [Berdoukas et al 2010, Farmaki et al 2011, Voskaridou et al 2011]. FBS0701, a novel, orally available member of the desazadesferrithiocin class of siderophore-related tridentate chelators, is currently in clinical development [Neufeld et al 2012].A recent study in a mouse model of severe hemochromatosis has demonstrated that the use of minihepcidins, small drug-like hepcidin agonists, in a hepcidin-deficient mouse could be beneficial in iron overload disorders used either alone for prevention or possibly as adjunctive therapy with phlebotomy or chelation [Ramos et al 2012].Induction of fetal hemoglobin synthesis can reduce the severity of β-thalassemia by improving the imbalance between alpha and non-alpha globin chains. Several pharmacologic compounds including 5-azacytidine, decytabine, and butyrate derivatives have had encouraging results in clinical trials [Pace & Zein 2006]. These agents induce Hb F by different mechanisms that are not yet well defined. Their potential in the management of β-thalassemia syndromes is under investigation [Perrine 2008, Boosalis et al 2011]. The efficacy of hydroxyurea treatment in individuals with thalassemia is still unclear. Hydroxyurea is used in persons with thalassemia intermedia to reduce extramedullary masses, to increase hemoglobin levels, and, in some cases, to improve leg ulcers [Levin & Koren 2011]. Hydroxyurea prevents hemolysis and hypercoagulability by modifying the defective hemoglobin synthesis and reducing thrombocytosis. A retrospective study found no pulmonary hypertension in 50 individuals with thalassemia intermedia treated with hydroxyurea for seven years [Karimi et al 2009, Taher et al 2010]. A good response, correlated with particular polymorphisms in the beta-globin cluster (i.e., C>T at -158 G gamma), has been reported in individuals with transfusion dependence [Bradai et al 2003, Yavarian et al 2004]. However, controlled and randomized studies are warranted to establish the role of hydroxyurea in the management of thalassemia syndromes. The possibility of correction of the molecular defect in hematopoietic stem cells by transfer of a normal gene via a suitable vector or by homologous recombination is being actively investigated. The most promising results in the mouse model have been obtained with lentiviral vectors [Persons 2009]. A clinical trial for β-thalassemia has begun in France, and one individual with transfusion-dependent HbE/beta-thalassemia has demonstrated a therapeutic effect after transplantation with autologous CD 34(+) cells, genetically modified with a beta-globin lentiviral vector [Kaiser 2009]. The levels of genetically modified cells increased from 2% in the first few months to 11% at 33 months post-transplant. The affected individual was last transfused on June 6, 2008, and four years after transplantation (despite being slightly anemic and undergoing repeated phlebotomies for the decrease of iron overload) does not require blood transfusions. However, most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 (a potential oncogene in various types of cancer) in erythroid cells. Even if this integration seems hitherto benign, the ethical evaluation of risk/benefit ratios of gene therapy in thalassemia is difficult at present [Cavazzana-Calvo et al 2010].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherAttempts at in utero transplantation using the father as a haploidentical donor have consistently failed.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Beta-Thalassemia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDHBB11p15.4
Hemoglobin subunit betaHbVar: A Database of Human Hemoglobin Variants and Thalassemias HBB @ LOVDHBBData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Beta-Thalassemia (View All in OMIM) View in own window 141900HEMOGLOBIN--BETA LOCUS; HBB 604131ALPHA-THALASSEMIANormal allelic variants. HBB, which spans 1.6 kb, contains three exons and both 5' and 3' untranslated regions. HBB is regulated by an adjacent 5' promoter, which contains a TATA, CAAT, and duplicated CACCC boxes, and an upstream regulatory element dubbed the locus control region (LCR). A number of transcription factors regulate the function of HBB, the most important of which is the erythroid Kruppel-like factor (EKLF), which binds the proximal CACCC box and whose knockout in the mouse leads to a thalassemia-like clinical picture. HBB is contained within the HBB gene cluster, which also includes the genes encoding the delta globin chain, A gamma and G gamma chains, and an HBB pseudogene. Pathologic allelic variants. β-thalassemias are heterogeneous at the molecular level. More than 200 disease-causing mutations have been identified to date. The large majority of mutations are simple single-nucleotide substitutions or deletion or insertion of oligonucleotides leading to a frameshift. Rarely, the β-thalassemias are the result of gross gene deletion (frequency of deletions may vary across populations). Despite marked molecular heterogeneity, the prevalent molecular defects are limited in each at-risk population (see Table 4), in which four to ten mutations usually account for most of the HBB disease-causing alleles:βº-thalassemia (complete absence of hemoglobin subunit beta production) alleles result from nonsense, frameshift, or (sometimes) splicing mutations. β+-thalassemia alleles (residual output of globin beta chains) are produced by mutations in the promoter area (either the CACCC or the TATA box), the polyadenylation signal, or the 5' or 3' untranslated region, or by splicing abnormalities. The complex β-thalassemias (delta-beta- and gamma-delta-beta-thalassemia) result from deletion of variable extent of the HBB gene cluster. β-thalassemia may also be produced by deletion of the LCR, leaving intact HBB itself. In rare instances, the β-thalassemia defect lies outside the β-globin gene cluster. Table 4. Selected HBB Pathologic Allelic VariantsView in own windowDNA Nucleotide Change 1(Alias 2) Protein Amino Acid Change 1At-Risk Populations Detection FrequencyReference Sequencesc.-136C>G (-87C>G) --Mediterranean91%-95%NM_000518.4 c.92+1G>A (IVS1-1G>A)--c.92+6T>C (IVS1-6T>C)--c.93-21G>A (IVS1-110G>A)--c.118C>T (cd39C>T)p.Gln39Xc.316-106C>G (IVS2-745C>G)--c.25_26delAA (cd8-AA)p.Lys8Valfs*13Middle Eastc.27_28insG (cd8/9+G)p.Ser9Valfs*13c.92+5G>C (IVS1-5G>C)--c.118C>T (cd39C>T)p.Gln39X c.135delC (cd44-C)p.Phe45Leufs*15c.315+1G>A (IVS2-1G>A)--c.-78A>G (-28A>G)--Thaic.52A>T (17A>T)p.Lys17X c.59A>G (19A>G)p.Asn19Ser (Hb Malay)c.92+5G>C (IVS1-5G>C)--c.124_127delTTCT (41/42-TTCT)p.Phe42Leufs*17c.316-197C>T (IVS2-654C>T)--c.-78A>G (-28A>G)--Chinesec.52A>T (17A>T)p.Lys17Xc.124_127delTTCT (41/42-TTCT)p.Phe42Leufs*17c.316-197C>T (IVS2-654C>T)--c.-138C>T (-88C>T)--African / African American75%-80%c.-79A>G (-29A>G)--c.92+5G>C (IVS1-5G>T)--c.75T>A (cd24T>A)p.Gly24Glyc.316-2A>G (IVS11-849A>G)--c.316-2A>C (IVS11-849A>C)--See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. The DNA nucleotide change designations follow current nomenclature guidelines. However, because the initiating methionine is not part of the mature beta-globin protein, the long-standing convention of numbering the amino acids is to begin with the next amino acid (Val). For consistency with the literature and the Globin Gene Server (globin.cse.psu.edu), the amino acid numbering in this table follows that convention.2. Variant designation that does not conform to current naming conventionsSilent mutations, which are characterized by normal hematologic findings and defined only by a mildly unbalanced α/β-globin chain synthesis ratio, result from mutation of the distal CACCC box, the 5' unbalanced region, the polyadenylation signal, and some splicing defects (see Table 5).Table 5. Mild and Silent HBB Mutations Causing β-ThalassemiaView in own windowMutation Type or Location Aliases 1 Standard Naming Conventions 2, 3 Mild β+ SilentDNA Nucleotide Change (Protein Amino Acid Change)Transcriptional mutants in the proximal CACC box -90 C>T -88 C>T -88 C>A -87 C>T -87 C>G -87 C>A -86 C>T -86 C>Gc.-140C>T c.-138C>T c.-138C>A c.-137C>T c.-137C>G c.-137C>A c.-136C>T c.-136C>G-101 C>T -92 C>Tc.-151C>T c.-142C>TTATA box -31 A>G -30 T>A -29 A>G c.-81A>G c.-80T>A c.-79A>G 5' UTR +22 G>A +10 -T +33 C>G c.-29G>A c.-41de>T c.-18C>G +1' A>Cc.-50A>CAlternative splicing cd19 A>C (Hb Malay) cd24 T>A c.56A>G (p.Asn19Ser) 4 c.72T>A (p.Gly24Gly) 4 cd27 G>T (Hb Knossos)c.82G>T (p.Ala27Ser) 4 Consensus splicing IVS1-6 T>C c.91+6T>CIntron IVS2-844 C>Gc.316-7C>G3' UTR +6 C>Gc.*6C>GPoly A site AACAAA AATGAA c.*110T>C c.*111A>GAATAAGc.*113A>GMild βº Frameshift cd6-A cd8-AA c.17delA (p.Glu6Glyfs*12) 4 c.25_26delAA (p.Lys8Valfs*13) 4 1. Nonstandard variant designations in common use (globin.cse.psu.edu)2. See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 3. Reference sequence is NM_000518 (www.ncbi.nlm.nih.gov/Genbank).4. The DNA nucleotide change designations follow current nomenclature guidelines. However, because the initiating methionine is not part of the mature beta-globin protein, the long-standing convention of numbering the amino acids is to begin with the next amino acid (Val). For consistency with the literature and the Globin Gene Server (globin.cse.psu.edu), the amino acid numbering in this table follows that convention.For more information, see Table A.Normal gene product. HBB encodes hemoglobin subunit beta. The heterodimeric protein HbA is made up of two globin alpha chains and two globin beta chains. Abnormal gene product. βº-thalassemia results from the absence of globin beta chains. In β+-thalassemia, the globin beta chain output is reduced to a variable extent, but the globin beta chains have a normal sequence.
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