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Estimates indicate that the prevalence among live births is 4.4% in the world. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. More than one thousand hemoglobin variants have been discovered to date.1 Although most do not cause disease, some variants affect the size, shape, and efficacy of red blood cells.2 We describe 2 years old female that was heterozygous of IVSI-5 mutation and homozygous α 3.7 triplication. Detects the 4 alpha-globin gene mutations common in the Filipino population. Alpha-thalassemia is an autosomal recessive condition that results from a deletion or dysfunction of alpha-globin chains. These alleles govern alpha globin production and if mutations lead to functional loss of one or more of alpha genes, alpha thalassemia occurs. Individuals who carry a mutation affecting α-globin genes on a single chromosome, associated with mild anemia are said to have ‘silent’ α-thalassemia (if one gene is involved) or α-thalassemia trait (when two genes are involved), while compound heterozygotes or homozygotes … The Hemoglobin Diagnostic Reference Laboratory at Boston Medical Center provides clinical, genetic, and laboratory correlation and consultation, and is one of only three labs in the United States to conduct hemoglobin diagnostics testing. A genetic polymorphism for a Bgl I endonuclease site near the alpha-globin-like pseudogene alpha-4 of C57BL/6 and C3H/HeN mice was used to show that alpha-4 was not affected by three independent mutations in which the adult globin genes alpha-1 and alpha-2 were deleted. Hemoglobin H disease occurs due to variants of three alpha globin genes (--/-a) and results in hemolysis with Heinz bodies, moderate anemia, and splenomegaly. A mutation in either gene could result in a structural hemoglobinopathy. 7KB deletion (n=27), followed by the SEA (n=4), the 20. The confirmation or discovery of those mutations is what confirms the diagnosis. This combination modulates hematological indices … This finding led to screening and follow up in first-degree relatives, twin brothers and a sister and parents to provide them with appropriate genetic counseling. Alpha thalassemia: Variants included in the analysis of the alpha-globin (HBA) gene cluster are the Constant Spring non-deletion variant and the following deletions: -alpha3.7, -alpha4.2, --alpha20.5, --SEA, --FIL, --THAI, --MED, and the HS-40 regulatory region. The –α 3.7 rightward deletion is the most frequent α-globin mutation but ααα (anti 3.7) triplication is relatively rare. Alpha Thalassemia ( HBA1 and HBA2) Deletion/Duplication with Reflex to Hb Constant Spring, Fetal. for alpha globin: HBA1 and HBA2. A total of 859 subjects were selected; genomic DNA was extracted and examined for the presence of mutations in the alpha‐globin genes. Alpha Globin Gene Mutation: A Major Determinant of Hydroxyurea Response in Transfusion-Dependent HbE-β-Thalassaemia. Inheritance of only one out of the four normal alpha-globin genes (-α/--) leads to a condition known as HbH disease, or alpha thalassemia intermedia. The loss of 3 alpha-globin genes results in abundant formation of HbH, which is characterized by a high ratio of beta globin to alpha globin and a 2-fold to 5-fold excess in beta-globin production. β-Thalassaemia mutations and α-globin gene deletions and triplications were detected by amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR) and Gap-PCR, respectively. Knowledge of the HBA1 and HBA2 For example, in beta thalassemia, mutations in beta globin gene cause deficiency of beta globin. --THAI, --FIL or --MED). The hemoglobin transports oxygen efficiently in a low oxygen environment. recombination events that fuse the two alpha globin genes together into one (Benz, 2018c). Please call 866-GENE-INFO to discuss the case, the patient’s indices, and additional testing options. 3003656. The main molecular test available for alpha thalassemia helps confirm common mutations such as deletions. Disease ranges in severity from mild abnormalities of erythrocytic indices to severe anemia. Hemoglobin subunit beta, (beta globin, β-globin, haemoglobin beta, hemoglobin beta) is a globin protein, coded for by the HBB gene, which along with alpha globin (), makes up the most common form of haemoglobin in adult humans, hemoglobin A (HbA). Sickle cell trait mainly co-inherits with alpha-globin gene mutation in the south and south central region of Iran. genes (-a/-a) or variants in the HBA1 and HBA2 globin genes on the same chromosome (--/aa) and results in mild microcytic anemia. This test is designed to detect copy-number changes in the α-globin gene cluster (deletions and duplications) of 28 different sequences in the HBA region. As a result, to rule out alpha-thalassemia as a cause of this patient’s anemia, molecular testing for mutations in the alpha-globin locus was performed. 1. Deletions account for approximately 90% of disease-causing alleles in … In addition, the assay detects the presence of the Constant Spring (Hb CS) mutation. Seyed Mohammad Bagher Hashemi-Soteh Biochemistry and Genetic Department, Immunogenetic Research Center, Molecular and Cell Biology Research Center, Medical Faculty, Mazandaran University of Medical Sciences, Sari, Iran. Detects 21 common alpha globin mutations. Deletion mutations involving one or both of the alpha-globin genes (designated HBA1 (alpha-1) and HBA2 (alpha-2)) in the alpha-globin gene cluster (located on chromosome 16p13) lead to reduced production of alpha-globin chains, Individuals can inherit a combination of deletional and non-deletional mutations. In hemoglobin H disease one parent carries one alpha globin gene mutation (deletion or point mutation), while the other parent carries a double deletion … The alpha 1- and alpha 2-globin gene initiation codon mutations result in similarly lowered levels of encoded mRNA. The human alpha-globin genes are paralogues, sharing a high degree of DNA sequence similarity and producing an identical alpha-globin chain. The Alpha-Globin Gene Deletion or Duplication assay (test code 16124X [or 16125X for New York State]) can detect other deletions or duplications of these genes. Alpha-thalassemia is a group of disorders of hemoglobin synthesis, caused by mutations or deletions in at least 1 of the 4 alpha-globin genes, leading to variably impaired alpha-globin chain production, with accumulation of the now excess and unpaired beta-globin chains. Four functional α-globin (HBA) alleles are present per diploid erythroblast, with two tandem HBA alleles at each 16p13.3 locus; these genes, HBA1 and HBA2, have identical coding sequences with some variation in the noncoding portion. A normal individual has four alpha-globin genes which is indicated as alphaalpha/alphaalpha. The mutations of alpha globin genes are generally evaluated in the two groups. In Israel, where alpha(o)-trait thalassemia is uncommon, it is of particular importance because of its phenotypic interactions with beta-thalassemia in hetero- and homozygotes. Sickle cell disease (SCD) is a structural and monogenetic genetic disorder due to a mutation that occurs in the globin β-chain, resulting in the formation of hemoglobin S (Hb S), a protein composed of two normal, and two β-type mutant chains. However, these mutations could also affect hemoglobin A production through AHSP-independent effects, including reduced binding to beta globin. With most of these variants are mutations in the alpha globin gene that result in an abnormally long alpha chain and an unstable hemoglobin molecules. We also speculate as to why long-range control of gene expression may have evolved in higher organisms. -α 3.7 and -α 4.2 deletions) or both copies (e.g. Alpha-thalassemia is a group of disorders of hemoglobin synthesis, caused by mutations or deletions in at least 1 of the 4 alpha-globin genes, leading to variably impaired alpha-globin chain production, with accumulation of the now excess and unpaired beta-globin chains. One, 2, 3, or 4 alpha-globin genes may be deleted or, less commonly, contain mutations. Question 2. One of the functions of alleles is governing the production of alpha-globin. Hemoglobin H disease results from mutations in three of the four alpha globin genes normally present. Rare syndromic or acquired forms of alpha thalassemia associated with ATRX mutations will not be detected. Nondeletional forms of alpha thalassemia in which the alpha-globin genes are intact are caused by mutations similar to those causing beta thalassemia and are relatively uncommon. Many mutations can affect the alpha globin gene, but the most common are gene deletions; As mentioned previously, there are 4 copies of the alpha gene in each somatic cell. Remember, everyone has two copies of these genes known as alleles. The inactivation of two alpha-globin genes causes a very mild microcytic, hypochromic anemia. There are two hemoglobin alpha chain genes, HBA1 and HBA2, in the alpha-globin gene cluster located at the end of the short arm of chromosome 16. If three of the four alpha-globin genes are functional, individuals are completely asymptomatic. 5 Alpha globin genes are duplicated on chromosome 16, so a normal individual has four copies. Our Laboratory is CAP and CLIA certified. The hematological picture of β-thalassemia heterozygotes with a triplicated α-globin gene arrangement is variable. A coexistence of sickle cell trait and beta-globin gene mutation was the frequent genotype in overall samples [57.5%]. Yuson3†. There are currently over 800 hemoglobin variants catalogued, of which approximately 300 are due to mutations in the alpha-globin gene. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Non- deletional alpha globin mutations may be pathogenic or benign; both may result in an abnormal protein detectable by hemoglobin evaluation. Mutation analysis of alpha‐globin genes revealed 27 different mutations. Pathogenic non-deletional mutations often have a more severe effect than single gene deletions. The mutations appear to occur at random; thus, either one of the 3 bases are replaced in the 199 known alpha-globin gene mutants. The most common mutations are large deletions that affect one or both genes on the locus. Seven variants were seen in 91.45% of all alpha‐1 and alpha‐2 mutations among patients in this study. Alpha (+) thalassemia results from mutation of a single alpha2 globin gene (-a/aa) and is clinically asymptomatic (silent carrier). The alpha globin gene cluster contains two highly homologous alpha globin genes, HBA1 and HBA2, that code for identical proteins. Epidemiology Additionally, non-deletion alleles are also common, especially in the Mediterranean area, which contain mutations producing highly unstable alpha globin variants unable to produce intact The deletion of one alpha-globin gene (-alpha/alphaalpha) is indicated as an alpha-thal-2 heterozygosity; the same nomenclature is used for mutations in either the alpha2- or alpha1-globin gene [alpha(T)alpha/alphaalpha or alphaalpha(T)/alphaalpha]. The alpha (HBA1, 141800; HBA2, 141850) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, HbA.Mutant beta globin that sickles causes sickle cell anemia ().Absence of beta chain causes beta-zero-thalassemia. Catherine Lynn T. Silao1,2*, Terence Diane F. Fabella1, Maria Liza T. Naranjo3, Mayceemae M. Barnuevo1, Carmencita D. Padilla1,2, and Ernesto dJ. Despite the similarity of these two mutations, the alpha 2 mutant results in a more severe loss of alpha-globin synthesis and a more severe clinical alpha-thalassemia phenotype than the corresponding alpha 1-globin gene mutation. An individual who inherits a mutation in one alpha-globin gene is a silent Human Hemoglobin Mutations: HbVar database A relational database of Hb variants and thalassemias, initially derived from Prof. Huisman's Syllabi (see next links) and regularly updated. [citation needed] Hemoglobin F is the primary hemoglobin produced by the fetus. Four alpha-globin genes are normally present (2 on each chromosome 16). consequence different mutations detected were categorized as +or 0, based on the records available in HbVar database [2]. Results. Alpha globin gene triplications result in three active alpha globin genes on a single chromosome. Table 1: Distribution of β-thalassemia carriers with and without δ-globin gene mutations among Malaysian ethnics. These are seen as general deletion with (+) and (0) phenotype and non-deletions with point mutation. The alpha 1- and alpha 2-globin gene initiation codon mutations result in similarly lowered levels of encoded mRNA. If there is the accumulation of gamma globin chain with the decrease of alpha globin … A combination of different alpha-globin gene mutations results in different clinical types of varying severity. The most common mutations causing alpha-thalassemia are large deletions. Methods A total of 40,808 blood samples from 14,332 families were obtained and analyzed for both hematological and molecular parameters. Hemoglobin H disease is the most severe non-fatal form of alpha-thalassemia, which is predominantly seen in the Mediterranean, Middle East, Southeast Asia, and southern China. Alpha globin gene mutations or deletions can be detected in the neonatal period because Hb F is composed of alpha and gamma globin chains. Alpha-thalassemia is caused by decreased synthesis of alpha-globin chains. Collapse Section The HBA1 gene provides instructions for making a protein called alpha-globin. One, 2, 3, or 4 alpha-globin genes may be deleted or, less commonly, contain variants. Michael F. Murray, in Emery and Rimoin's Principles and Practice of Medical Genetics, 2013 39.5.4 Alpha-Globin (HBA1 and HBA2). SUMMARY: The review asks how remote elements regulate alpha globin expression and how natural mutations interfere with this mechanism to cause alpha thalassemia. Despite the similarity of these two mutations, the alpha 2 mutant results in a more severe loss of alpha-globin synthesis and a more severe clinical alpha-thalassemia phenotype than the corresponding alpha 1-globin gene mutation. measured. Institute of Haematology and Transfusion Medicine, Medical College, Kolkata, India. Alpha globin gene variants are unique for every population (Cheerva 2013). In addition, approximately 5% of alpha-thalassemia is caused by point mutations. The compound heterozygous condition produces a severe shortage of alpha globin chains. alpha-Globin Mutations and Rearrangements in Israel: PCR-Based Analysis Reveals Ethnic Diversitya Alpha Globin Multiplex PCR-based mutation detection. Alpha globin amino acid substitutions H103Y, H103R, F117S, and P119S impaired interactions with both AHSP and beta globin. Over half of the alpha-globin structural variants reported to date are only characterized at the amino acid level. The presence of other non-deletional mutations, like point mutations, in the alpha-globin gene cannot be excluded as the assay does not detect these changes. It may mean that the cell does not produce the protein the body needs. The alpha globin gene cluster on one of the two chromosomes 16 has both alpha globin genes deleted. Alpha-thalassemia is among the world's most common single gene disorders, caused primarily by gene deletions. mutations identified in different ethnic groups/populations during prenatal diagnosis for beta-thalassemia in Malaysia; Data show the frequent juxtaposition of active alpha- and beta-globin genes and of homologous alpha-globin loci that occurs at nuclear speckles and correlates with transcription. These two alpha-globin genes are located close together in a region of chromosome 16 known as the alpha-globin locus. Each gene has two copies, one inherited from each parent for each gene (αα/αα). This protein is also produced from a nearly identical gene called HBA2. A number sign (#) is used with this entry because of evidence that alpha-thalassemia is caused by mutations in the alpha-globin genes (HBA1, 141800; HBA2, 141850). Data on the effect of alpha globin gene variation on the concentration of iron on transfusion dependent Saudis are scanty. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. Reporting Name. Author information. – Alpha globin sequencing • Beta thalassemia – Beta globin sequencing • The test examines the complete beta globin coding sequence, the splice sites and other intronic regions known to harbor mutations, the proximal promoter region, and the 5’ and 3’UTR regions. Thus, humans have 4 alpha globin gene copies (two from each parent) and 2 beta globin gene copies (one from each parent). A one-way between groups ANOVA was conducted to compare the hematological parameters of Hb, RBC, MCV, MCH, … In the Philippines, however, no study has been done to identify the underlying α-thalassemia mutations. On the other chromosome 16, the alpha1 gene has the Constant Spring mutation. • Clinical sensitivity is up to 97% based on the ethnicity Affiliations. My patient's result indicates the deletion of 2 alpha-globin genes but doesn't identify the name of the mutation or differentiate between cis (both gene deletions in one chromosome) and trans (one gene deletion in each chromosome). What can I do? Available Separately. There are more than 15 different genetic mutations that result in decreased production of alpha globin, usually through functional deletion of 1 or more of the 4 alpha-globin genes. Alpha-thalassemia is characterized by a deficit in the production of the α-globin chains of hemoglobin. Alpha-globin gene mutation spectrum in patients with microcytic hypochromic anemia from Mazandaran Province, Iran. Four alpha-globin genes are normally present (2 on each chromosome 16). Point mutations in the alpha 1 and alpha 2 genes may be present. Alpha-Globin Gene Sequencing (test code 16116X [16117X for NY]) can detect point mutations in these genes. Please call 866-GENE-INFO to discuss the case, the patient’s indices, and additional testing options. Question 2. 2 authors. The inactivation of one alpha-globin gene is insignificant. Some rare forms of alpha-thalassemia are due to point mutations (non-deletional alpha-thalassemia). There is one beta gene on each chromosome 11 (one inherited from the mother and one from the father). Results A high prevalence of α- and β-globin gene mutations was found. Hemoglobinopathies. Typically, individuals with mutations in more of their alpha globin genes have more severe symptoms. In adults, hemoglobin normally consists of four protein subunits: two subunits of beta-globin and two subunits of a protein called alpha-globin, which is produced from another gene called HBA. Phenotypically, these deletions result in 4 categories of disease expression: Note=The disease is caused by variants affecting the gene represented in this entry. Deletions account for approximately 90% of disease-causing alleles in alpha thalassemia. The loss of function of three alpha-globin genes is called hemoglobin H disease. The two human alpha-globin genes, alpha 1 and alpha 2 located 3.4 kilobases apart on chromosome 16, encode identical alpha-globin proteins. An individual who carries two alpha-globin gene mutations and two functional alpha-globin genes is a carrier of the alpha-thalassemia trait, and may be unaffected or only mildly affected. The suggestion that alpha(+)-thalassemia has achieved a high frequency in some populations as a result of selection by malaria is based on a number of epidemiologic studies. The different forms of alpha thalassemia are described below. Alpha-globin is an essential component of the hemoglobin tetramer, beginning in the early stages of embryonic development. This study aimed to determine the common HBA1 and HBA2 mutations in Filipino patients suspected with α-thalassemia. Alpha-Globin Gene Sequencing (test code 16116X [16117X for NY]) can detect point mutations in these genes. This syndrome is a compound heterozygous state of the alpha globin gene cluster. The alpha globin gene cluster on one of the two chromosomes 16 has both alpha globin genes deleted. On the other chromosome 16, the alpha1 gene has the Constant Spring mutation. The Alpha-Globin Gene Sequencing assay (test code 16116X [or 16117X for New York State) can detect point mutations in these genes. Alpha-Globin Gene Analysis (ATHL) No. The HBA1 gene provides instructions for making a protein called alpha-globin. Alpha (0) thalassemia (trait) is caused by mutation of both alpha2 globin genes (-a/-a), or mutations in the alpha1 and alpha2 globin genes on the same chromosome, (--/aa) and results in mild microcytic anemia. Because of the repetitive nature of this gene cluster, the alpha-globin genes are prone to deletion. Genetic counseling may be advised for some patients. Definition. the last 10 years, in The Adult Thalassemia Unit of “Hippokration” Hospital, Thessaloniki, Northern Greece. The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. Loss of some or all of these alleles results in the various forms of alpha thalassemia. Alpha-Globin Common Mutation Analysis - Alpha Thalassemia is a common hereditary trait and disease among individuals of Asian heritage. This syndrome is a compound heterozygous state of the alpha globin gene cluster. Individuals carrying both a deletion and duplication within the alpha globin gene cluster may appear to have a normal number of alpha globin gene copies. GeneReviews: Beta-Thalassemia. Mutations in the alpha globin gene cluster are predominantly large deletions causing the loss of either one copy of the alpha-globin gene (e.g. [ 16 , 17 ] Additionally, non-deletional mutations generally cause more severe symptoms than deletional mutations. Nondeletional mutations are more severe. We’re also an integral part of The Center of Excellence in Sickle Cell Disease and are associated Objective To reveal the familial prevalence and molecular variation of α- and β-globin gene mutations in Guangdong Province. These two alpha-globin genes are located close together in a region of chromosome 16 known as the alpha-globin locus. In the Eastern province of Saudi Arabia, thalassemia is highly common. Alpha(+) thalassemia is subclassified into the following three general forms … Gene Mutation is a persistent deviation/change in the DNA sequence that forms a gene.Such mutations can affect from one structural element of DNA to a large segment of a chromosome containing a number of genes. Alpha thalassemia is the result of deficient or absent synthesis of alpha globin chains, leading to excess beta globin chains. Additional Technical Information. An individual with one alpha-globin gene mutation and three functional alpha-globin genes is a silent carrier. Alpha (0) thalassemia (trait) is caused by variants of both HBA2 globin. 1Institute of Human Genetics, National Institutes of Health. 2 KB deletion (n=4), the Dutch deletion (n=3) and alpha triplication (n=3). Test ID. A Syllabus of Human Hemoglobin Variants (1996) Most of A Syllabus of Thalassemia Mutations (1997) Database of Experimental Results on Gene Expression: dbERGE II My patient has 5 alpha-globin gene copies (an alpha globin triplication). These results indicated that alpha-4 might not be located adjacent to the adult alpha-globin genes on chromosome 11. Other point mutations, and variants in other genes, will not be detected by this assay. This is the most common form of HbH disease. Because alpha globin … ATHL. Alpha Thalassemia Alpha Thalassemia, HBA DD, Alpha thalassemia, alpha globin mutations, alpha globin gene analysis, A globin, ALPHA THAL, AG FGA, Hemoglobinopathies 3003651 Alpha Thalassemia ( HBA1 and HBA2 ) Deletion/Duplication with Reflex to Hb Constant Spring Point mutations within the alpha-globin genes account for the remaining 10% of mutations. This protein is also produced from a nearly identical gene called HBA2. In 52 samples we found mutations on the alpha-globin chains, most often the 3. alpha globin production requires all 4 alleles. https://ojrd.biomedcentral.com/articles/10.1186/s13023-020-01429-1 Alpha-thalassemia is caused by mutations, usually deletions, in the alpha-globin gene cluster.1 Inheritance is usually autosomal recessive.3 Each person has two HBA genes, HBA1 and HBA2. Common deletional forms of alpha globin mutations (HBA), i.e., 3.7kb deletion alpha2 gene (-3.7), 4.2kb deletion alpha2 gene (-4.2), 20.5kb deletion of alpha1 and alpha2 genes (--20.5), Thus, phenotypes increase in severity as the number of functional alpha genes decreases Figure 2: a) Electropherogram showing heterozygous δcd 56 GGC>GAC (HbA2-Shah Alam); b) CE data of HbA2-Shah Alam revealed an abnormal peak on zone 6. Deletional HbH disease occurs when a combination of deletion mutations remove three of the four genes that express the alpha-globin protein. A few large deletions encompassing … Similarly, there is deficiency of alpha globin due to nonfunctioning alpha globin genes in alpha thalassemia. mutations are autosomal recessive. Alpha Globin StripAssay. There are over 200 mutations identified as the culprits for causing thalassemias. Lists tests that may or may not be performed, at an additional charge, depending on the result and interpretation of the initial tests. Patients were categorised as good (41.5%), moderate (31.7%), and poor responders (26.8%) based on their decrease in Yes. Alpha thalassemia is caused by mutations in the alpha globin gene locus on chromosome 16. Mutations in the alpha genes are transferred to offspring in an autosomal recessive mode. Common Alpha Globin Genes (HBA1 and HBA2) Mutations in Filipino Patients with Alpha Thalassemia. Two of the remaining seven samples showed new alpha Thalassemia mutations which have not been described yet. We analyzed 6 human alpha globin variants with altered AHSP contact surfaces. 5 KB deletion (n=4), the 4. In addition, the patient had α gene triplication (αααanti 3.7/αα) caused by double heterozygosity for a 3.7 kb fragment that contained only the hemoglobin alpha globin gene-2 gene. Diagnostic errors can occur due to rare sequence variations. It has only recently become possible to assign an alpha-chain mutant to one of these two loci by using recombinant DNA technology. Variations in three out of four alpha‐globin genes (deletion or point mutation) cause HbH disease, which is characterized from mild to severe anemia and remarkably unbalanced globin … Biswas S 1, Ray R 1, Roy K 2, Bandyopadhyay A 2, Ghosh K 3, Bhattacharyya M 4. Types of alpha-thalassemia: Alpha thalassemia are classified on the basis of severity of symptoms: HBA DD, Alpha thalassemia, alpha globin mutations, alpha globin gene analysis, A globin. Reflex Tests. A total of 166 transfusions dependent β-thalassemia were included in this study to understand association between the alpha globin gene variation and concentration of iron. Alpha (α) thalassemia results from the absence/reduced synthesis of the α-globin subunit of hemoglobin (Hb). Diversity of alpha-globin mutations and clinical presentation of alpha-thalassemia in Israel. Alpha thalassemia is caused by deletions of alpha-globin genes, and beta thalassemias are caused by a point mutation in splice site and promoter regions of the beta-globin gene on chromosome 11. Turnaround time: 4 weeks 2.
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