Hemoglobin - Beta Locus

Alternative Names

  • HBB

Associated Diseases

Beta-Thalassemia
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OMIM Number

141900

NCBI Gene ID

3043

Uniprot ID

P68871

Length

3,932 bases

No. of Exons

3

No. of isoforms

1

Protein Name

Hemoglobin subunit beta

Molecular Mass

15998 Da

Amino Acid Count

147

Genomic Location

chr11:5,225,464-5,229,395

Gene Map Locus
11p15.4

Description

The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. [From RefSeq]

Epidemiology in the Arab World

View Map
Variant NameCountryGenomic LocationClinical SignificanceCondition(s)HGVS ExpressionsdbSNPClinvar
Hb Beirut NM_000518.5:c.380T>CLebanonNC_000011.10:g.5225662A>GLikely Benign,Uncertain SignificanceNG_059281.1:g.6410T>C; NM_000518.5:c.380T>C; NP_000509.1:p.Val127Ala3392539115106
Hb Casablanca NM_000518.4:c.[197A>T;367T>C]MoroccoNC_000011.10:g.[5226695T>A;5225675A>G]Beta-ThalassemiaNG_059281.1:g.[5377A>T;6397T>C]; NM_000518.4:c.[197A>T;367T>C]; NP_000509.1:p.[Lys66Met;Phe123Leu]33932548 33971848446744
Hb Doha NM_000518.5:c.5T>AQatarNC_000011.10:g.5227017A>TUncertain SignificanceNG_059281.1:g.5055T>A; NM_000518.5:c.5T>A; NP_000509.1:p.Val2Glu3394993015159
Hb D-Punjab NM_000518.5:c.364G>CUnited Arab EmiratesNC_000011.10:g.5225678C>GBenign,Likely Pathogenic,Pathogenic,Uncertain SignificanceSickle Cell Anemia; Beta-ThalassemiaNG_000007.3:g.71938G>C; NM_000518.5:c.364G>C; NP_000509.1:p.Glu122Gln3394626715152
Hb Iraq-Halabja NM_000518.5:c.32C>TIraqchr11:5226990Beta-ThalassemiaNG_059281.1:g.5082C>T; NM_000518.5:c.32C>T; NP_000509.1:p.Ala11Val3394745715571
Hb Knossos NM_000518.5:c.82G>TPalestineNC_000011.10:g.5226940C>ALikely Pathogenic,PathogenicBeta-ThalassemiaNG_059281.1:g.5132G>T; NM_000518.5:c.82G>T; NP_000509.1:p.Ala28Ser3542404015239
Hb Malay NM_000518.5:c.59A>GKuwaitchr11:5226963PathogenicBeta-ThalassemiaNG_059281.1:g.5109A>G; NM_000518.5:c.59A>G; NP_000509.1:p.Asn20Ser3397204715258
Hb Monroe NM_000518.5:c.92G>CIraq; Lebanon; United ...NC_000011.10:g.5226930C>GPathogenicBeta-ThalassemiaNG_059281.1:g.5142G>C; NM_000518.5:c.92G>C; NP_000509.1:p.Arg31Thr3396010315234
Hb Muscat NM_000518.5:c.94C>GOmanNC_000011.10:g.5226798G>CNG_059281.1:g.5274C>G; NM_000518.5:c.94C>G; NP_000509.1:p.Leu32Val3395655515509
Hb O-Arab NM_000518.5:c.364G>AMoroccoNC_000011.10:g.5225678C>ALikely Pathogenic,PathogenicNG_059281.1:g.6394G>A; Hb O-Arab NM_000518.5:c.364G>A; NP_000509.1:p.Glu122Lys3394626715292
Hb Summer Hill NM_000518.5:c.157G>CLebanonNC_000011.10:g.5226735C>GUncertain SignificanceNG_059281.1:g.5337G>C; NM_000518.5:c.157G>C; NP_000509.1:p.Asp53His3396188615362
Hb Tacoma NM_000518.5:c.93G>TUnited Arab EmiratesNC_000011.10:g.5226799C>APathogenic,Uncertain SignificanceNG_000007.3:g.70817G>T; NM_000518.5:c.93G>T; NP_000509.1:p.Arg31Ser113507115368
Hb Tizi-Ouzou NM_000518.5:c.88G>AAlgeriachr11:5226934Uncertain SignificanceNG_059281.1:g.5138G>A; NM_000518.5:c.88G>A; NP_000509.1:p.Gly30Ser3397427715615
Hb Tripoli NM_000518.5:c.80A>CAlgeriachr11:5226942Likely Pathogenic,PathogenicNG_059281.1:g.5130A>C; NM_000518.5:c.80A>C; NP_000509.1:p.Glu27Val3391511215614
Hb Tsukumi NM_000518.5:c.349C>TMoroccoNC_000011.10:g.5225693G>ABeta-ThalassemiaNG_059281.1:g.6379C>T; NM_000518.5:c.349C>T; NP_000509.1:p.His117Tyr3404976415582
HbS NM_000518.5:c.20A>TArab; Bahrain; Oman; U...NC_000011.10:g.5227002T>ALikely Benign,Pathogenic,Protective,Uncertain SignificanceSickle Cell AnemiaNG_059281.1:g.5070A>T; NM_000518.5:c.20A>T; NP_000509.1:p.Glu7Val33415333
NG_000007.3:g.71609_72227delUnited Arab EmiratesNC_000011.10:g.5225389_5226007delPathogenicBeta-ThalassemiaNG_000007.3:g.71609_72227del38701
NG_059281.1:g.4962G>CLebanonNC_000011.10:g.5227110C>GUncertain SignificanceBeta-ThalassemiaNG_059281.1:g.4962G>C; NG_059281.1:g.4962G>C1245744370
NM_000518.4:c.114G>AArabNC_000011.10:g.5226778C>TLikely Pathogenic,PathogenicBeta-ThalassemiaNG_000007.3:g.70838G>A; NM_000518.4:c.114G>A; NP_000509.1:p.Trp38Ter3397493615405
NM_000518.5:c.*110_*114delEgypt; Oman; United Ar...chr11:5225486_5225490PathogenicBeta-ThalassemiaNG_059281.1:g.6584_6588del; NM_000518.5:c.*110_*114del3594913015506
NM_000518.5:c.*113A>GUnited Arab EmiratesNC_000011.10:g.5225485T>CLikely Pathogenic,PathogenicBeta-ThalassemiaNG_000007.3:g.72131A>G; NM_000518.5:c.*113A>G3398547215473
NM_000518.5:c.0_92+25delLebanonchr11:5226905-5227197PathogenicBeta-ThalassemiaNG_059281.1:g.4875_5167del; NM_000518.5:c.0_92+25del1564875707590887
NM_000518.5:c.110delBahrainchr11:5226782PathogenicBeta-ThalassemiaNG_059281.1:g.5290del; NM_000518.5:c.110del; NP_000509.1:p.Pro37fs26760729715424
NM_000518.5:c.112delKuwait; Lebanon; Unite...NC_000011.10:g.5226781delPathogenicBeta-ThalassemiaNG_059281.1:g.5292del; NM_000518.5:c.112del; NP_000509.1:p.Trp38fs6375053215431
NM_000518.5:c.114delUnited Arab EmiratesNC_000011.10:g.5226779delLikely PathogenicBeta-ThalassemiaNG_000007.3:g.70838del; NM_000518.5:c.114del; NP_000509.1:p.Pro37_Trp38insTer281865474
NM_000518.5:c.118C>TBahrain; Comoros; Iraq...NC_000011.10:g.5226774G>APathogenicBeta-ThalassemiaNG_059281.1:g.5298C>T; NM_000518.5:c.118C>T; NP_000509.1:p.Gln40Ter1154940715402
NM_000518.5:c.126_129delBahrainchr11:5226765-5226768Likely Pathogenic,PathogenicBeta-ThalassemiaNG_059281.1:g.5306_5309del; NM_000518.5:c.126_129del; NP_000509.1:p.Phe42fs8035682115417
NM_000518.5:c.135delArab; Bahrain; Iraq; K...NC_000011.10:g.5226758delPathogenicBeta-ThalassemiaNG_059281.1:g.5315del; NM_000518.5:c.135del; NP_000509.1:p.Phe46fs8035682015415
NM_000518.5:c.-137C>GLebanonchr11:5227158Likely Pathogenic,PathogenicBeta-ThalassemiaNG_059281.1:g.4914C>G; NM_000518.5:c.-137C>G3394137715464
NM_000518.5:c.-138C>ABahrain; United Arab E...chr11:5227159Likely Pathogenic,PathogenicSickle Cell Anemia; Beta-ThalassemiaNG_059281.1:g.4913C>A; NM_000518.5:c.-138C>A33944208393701
NM_000518.5:c.-138C>TLebanonchr11:5227159Likely Pathogenic,PathogenicBeta-ThalassemiaNG_059281.1:g.4913C>T; NM_000518.5:c.-138C>T3394420815460
NM_000518.5:c.-151C>TKuwait; United Arab Em...NC_000011.10:g.5227172G>APathogenicBeta-ThalassemiaNG_059281.1:g.4900C>T; NM_000518.5:c.-151C>T6375120815461
NM_000518.5:c.17_18delIraq; Lebanon; United ...NC_000011.10:g.5227004_5227005delPathogenicBeta-ThalassemiaNG_059281.1:g.5067_5068del; NM_000518.5:c.17_18del; NP_000509.1:p.Pro6fs3488988215422
NM_000518.5:c.20delAlgeria; Saudi Arabiachr11:5227002PathogenicBeta-ThalassemiaNG_059281.1:g.5070del; NM_000518.5:c.20del; NP_000509.1:p.Glu7fs6374981915418
NM_000518.5:c.25_26delArab; Iraq; Kuwait; Le...NC_000011.10:g.5226996_5226997delPathogenicBeta-ThalassemiaNG_059281.1:g.5075_5076del; NM_000518.5:c.25_26del; NP_000509.1:p.Lys9fs3549710215413
NM_000518.5:c.251delArab; United Arab Emir...NC_000011.10:g.5226643delPathogenicBeta-ThalassemiaNG_000007.3:g.70975del; NM_000518.5:c.251del; NP_000509.1:p.Gly84AlafsTer619392255536306
NM_000518.5:c.27dupArab; Bahrain; Iraq; J...NC_000011.10:g.5226995dupPathogenicBeta-ThalassemiaNG_059281.1:g.5077dup; NM_000518.5:c.27dup; NP_000509.1:p.Ser10fs3569960636308
NM_000518.5:c.2T>CComoroschr11:5227020Likely Pathogenic,PathogenicBeta-ThalassemiaNG_059281.1:g.5052T>C; NM_000518.5:c.2T>C; NP_000509.1:p.Met1Thr3394184936310
NM_000518.5:c.315+1G>AArab; Bahrain; Comoros...NC_000011.10:g.5226576C>TPathogenicBeta-ThalassemiaNG_059281.1:g.5496G>A; NM_000518.5:c.315+1G>A3394577715438
NM_000518.5:c.316-106C>GEgypt; Jordan; Lebanon...chr11:5225832PathogenicBeta-ThalassemiaNG_059281.1:g.6240C>G; NM_000518.5:c.316-106C>G3469059915457
NM_000518.5:c.316-3C>AEgypt; United Arab Emi...NC_000011.10:g.5225729G>TLikely Pathogenic,PathogenicBeta-ThalassemiaNG_059281.1:g.6343C>A; NM_000518.5:c.316-3C>A3391341315451
NM_000518.5:c.316-8T>GAlgeriachr11:5225734PathogenicBeta-ThalassemiaNG_059281.1:g.6338T>G; NM_000518.5:c.316-8T>G3479359415453
NM_000518.5:c.332T>CUnited Arab EmiratesNC_000011.10:g.5225710A>GPathogenicBeta-ThalassemiaNG_000007.3:g.71906T>C; NM_000518.5:c.332T>C; NP_000509.1:p.Leu111Pro3525648915352
NM_000518.5:c.47G>ABahrain; Iraq; United ...NC_000011.10:g.5226975C>TPathogenicBeta-ThalassemiaNG_059281.1:g.5097G>A; NM_000518.5:c.47G>A; NP_000509.1:p.Trp16Ter6375078315403
NM_000518.5:c.-50A>CSaudi Arabiachr11:5227071Likely Pathogenic,PathogenicBeta-ThalassemiaNG_059281.1:g.5001A>C; NM_000518.5:c.-50A>C3430519536292
NM_000518.5:c.68_74delIraqchr11:5226949-5226955PathogenicBeta-ThalassemiaNG_059281.1:g.5118_5124del; NM_000518.5:c.68_74del; NP_000509.1:p.Glu23ValfsTer37281864898869360
NM_000518.5:c.-78A>CIraqchr11:5227099PathogenicBeta-ThalassemiaNG_059281.1:g.4973A>C; NM_000518.5:c.-78A>C3393174615470
NM_000518.5:c.-80T>ALebanonchr11:5227101Likely Pathogenic,PathogenicBeta-ThalassemiaNG_059281.1:g.4971T>A; NM_000518.5:c.-80T>A3398085715467
NM_000518.5:c.90C>TLebanonchr11:5226932PathogenicBeta-ThalassemiaNG_059281.1:g.5140C>T; NM_000518.5:c.90C>T; NP_000509.1:p.Gly30=3557800238682
NM_000518.5:c.92+1G>A Bahrain; Egypt; Iraq; ...chr11:5226929PathogenicBeta-ThalassemiaNG_059281.1:g.5143G>A; NM_000518.5:c.92+1G>A3397144015436
NM_000518.5:c.92+1G>CUnited Arab EmiratesNC_000011.10:g.5226929C>GPathogenicBeta-ThalassemiaNG_000007.3:g.70687G>C; NM_000518.5:c.92+1G>C33971440869246
NM_000518.5:c.92+2T>CAlgeriachr11:5226928PathogenicBeta-ThalassemiaNG_059281.1:g.5144T>C; NM_000518.5:c.92+2T>C3395687936334
NM_000518.5:c.92+5G>AAlgeriachr11:5226925Likely Pathogenic,PathogenicBeta-ThalassemiaNG_059281.1:g.5147G>A; NM_000518.5:c.92+5G>A3391521715449
NM_000518.5:c.92+5G>CArab; Bahrain; Iraq; K...NC_000011.10:g.5226925C>GPathogenicBeta-ThalassemiaNG_059281.1:g.5147G>C; NM_000518.5:c.92+5G>C3391521715447
NM_000518.5:c.92+6T>CEgypt; Iraq; Jordan; K...NC_000011.10:g.5226924A>GPathogenicBeta-ThalassemiaNG_059281.1:g.5148T>C; NM_000518.5:c.92+6T>C3572477515450
NM_000518.5:c.92G>ALebanonchr11:5226930Likely PathogenicBeta-ThalassemiaNG_059281.1:g.5142G>A; NM_000518.5:c.92G>A; NP_000509.1:p.Arg31Lys3396010336337
NM_000518.5:c.93-1G>AEgyptchr11:5226800PathogenicBeta-ThalassemiaNG_059281.1:g.5272G>A; NM_000518.5:c.93-1G>A3394300115446
NM_000518.5:c.93-1G>COman; United Arab Emir...NC_000011.10:g.5226800C>GPathogenicBeta-ThalassemiaNG_059281.1:g.5272G>C; NM_000518.5:c.93-1G>C33943001439166
NM_000518.5:c.93-21_96delArab; Bahrain; Kuwait;...NC_000011.10:g.5226796_5226820delPathogenicBeta-ThalassemiaNG_059281.1:g.5252_5276del; NM_000518.5:c.93-21_96del63750223632854
NM_000518.5:c.93-21G>ABahrain; Comoros; Egyp...NC_000011.10:g.5226820C>TPathogenicBeta-ThalassemiaNG_059281.1:g.5252G>A; NM_000518.5:c.93-21G>A3500422015454
NM_000518.5:c.93-3T>GSaudi Arabiachr11:5226802PathogenicBeta-ThalassemiaNG_059281.1:g.5270T>G; NM_000518.5:c.93-3T>G3452784636341

Other Reports

Bahrain

Dash et al. (1996) were the first to describe hemoglobin C (HbC) in a Bahraini family. HbC was detected in the pregnant mother, who was Egyptian in origin, by hemoglobin electrophoresis in acid agar gel and confirmation by the "Iso Lab-Hemocard" monoclonal antibody test for HbC. Hemoglobin quantitation was made by HPLC showing HbC 32.2%, HbA2 2.8%, HbF 0.5%, and HbA 64.5%. Her peripheral blood film showed microcytic hypochromic red cells with some target cells. One of her children, a boy, also had the HbC trait.

During the study of the incidence of cystic fibrosis in Bahrain, Al Arrayed and Abdulla (1996) detected 27 patients with cystic fibrosis (25 were Bahrainis). Of those, one patient had sickle/beta-thalassemia. Three years later, Al Arrayed et al. (1999) analyzed 500 formats for 500 clients taken at random. About 23.2% of the parents were first cousins, 1.5% were second cousins, and 3% were far relatives. The frequency of beta thalassemia was 2%. Average HbA2 level in beta thalassemia trait was 5.6%.

Jassim and Al Arrayed (2006) studied the different molecular determinants that might cause an extremely mild form of sickle cell/beta-thalassemia syndrome in the Bahraini population. Blood samples of two non-related Bahraini girls were tested by PCR-restriction fragment polymorphism (PCR-RFLP), denaturing gradient gel electrophoresis (DGGE), and differential PCR amplification. Three different molecular determinants were found in their beta globin gene. The first one was the compound heterozygosity for the sickle cell mutation and nt-88 (C-A) mutation. The second determinant was the presence of HbS haplotype associated high HbF expression. The third determinant was the co-inheritance of alpha thalassemia.

Egypt

Sadek (1998) reported two females from a consanguineous family from Egypt with bilateral congenital choanal atresia. The patients also presented features of vitamin D resistant rickets. Their mother had beta-thalassemia minor.

Mahran et al. (1999) performed a prenatal diagnosis to identify mutations of the beta-globin gene in affected Egyptian families by using DNA PCR-amplification refractory mutation system (ARMS) and, therefore, achieving a preventive program. The study included 24 families, of which the at-risk couples, their diseased offspring(s) and 24 amniotic fluid samples from the ongoing pregnancies were tested (192 chromosomes) at molecular bases. The success rate of amniocentesis was 96%. Hematological studies were also performed. Consanguinity was observed in 13 families (54.16%). Of the total studied chromosomes, 122 were mutant (58 mutant chromosomes among patients, 48 for the heterozygote parents, 15 for the heterozygote fetuses, and only one chromosome of amniotic fluid samples was uncharacterized). The most common three mutations among 24 probands were beta-zero IVS 1 nt 1 (G-A), beta-plus IVS 1 nt 110 (G-A), and beta-plus IVS 1 nt 6 (T-C), which constituted 68.53% of all mutations. In 2% of the 24 probands the allele could not be characterized. It was found that homozygous beta-zero IVS 1 nt 1 (G-A) was the most frequent genotype among the 24 beta-thalassemia probands (30.76%). This mutation is followed by the homozygous beta-plus IVS 1 nt 110 (G-A; 23.07%), the compound heterozygote beta-zero IVS 1 nt 1 (G-A) with beta-plus IVS 1 nt 110 (G-A) and beta-plus IVS 1 nt 6 (T-C; 7.69% each). The highest mean of HbF level was in the beta-zero/beta-plus group (51.9%). The beta-zero/beta-zero group had the highest means of HbA level (81.5%), MCV level (80.9 fL), and MCH level (27.4 pg). Mahran et al. (1999) explained the correlation between phenotypes and genotypes on the basis that the clinical severity of beta-thalassemia was mainly dependant on the degree of beta-chain deficiency. Also, it was found that the coinheritance of hemoglobin Constant Spring could significantly reduce the severity of the disease. [Mahran M, Khalifa AS, Shawky RM, Abousenna I, Rifaat M, Kamal TM. Prenatal diagnosis of beta-thalassemia mutations in at-risk Egyptian families by ARMS-PCR. Egyptian J of Pediatr. 1999; 16(3):441-56.]

[See also: Bahrain > Dash et al, 1996].

Iraq

Gutman et al. (1978) described two maternal male cousins in a Jewish Iraqi family with dyskeratosis congenita and megaloblastic bone marrow. One cousin had pancytopenia while the other had thrombocytopenia. The kindred displayed a deficiency of glucose-6-phosphate dehydrogenase (G6PD) and a beta-thalassemia trait. Chromosomal studies showed a 46XY karyotype in both cases; however, nonspecific numerical aberrations and structural abnormalities were found in the first and in the second case, polyploidy was seen in four of 60 cells.

[See also: Kuwait > Adekile et al., 2005].

Jordan
Kuwait

Mulla and Chrobak (1973) reported the first Arab cases of hemoglobin C disease in Kuwait. The two cases consisted of two families, one Kuwaiti and the other Jordanian.

Kazazian and Boehm (1988) found a deletion of 17 nucleotides that removed the acceptor splice site from IVS1 in a Kuwaiti patient.

Al Mazidi (1996) scanned 40 children with beta-thal for various endocrine disorders. The patients' age range was (14-30) and 60% of them were Kuwaitis. The list of disorders among these patients included short stature (45%), delayed and or arrested puberty (45%), hypoparathyroidism (15%), hypothyroidism (8%), diabetes mellitus (5%), and multiple endocrine disorders (38%). [Al Mazidi Z. Endocrine disorders in B thalassemia major in Kuwait. Kuwait Med J. 1996; 28(3):252-5.]

Al-Fuzae et al. (1998) carried out a retrospective and prospective study of 129 patients with beta-thal major seen between 1965 and 1995 in a single hospital in Kuwait. About 80% of the patients were products of consanguineous unions. Bone marrow transplantation was performed in 11 of these patients. Although there was no BMT-related mortality, three cases of graft rejection and two of chronic graft-versus-host disease were noticed. With regard to hepatitis infection, 42 patients were found to be Heptitis C seropositive, while nine were positive for HBsAg.

Lebanon

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.

Zahed et al., 2002 conducted RFLP and sequence haplotype analysis to study the chromosomal background of 31 unrelated Lebanese subjects with IVS-I-110 (G>A) or codon 39 (C>T) beta-thalassemia mutations. Upon comparing the results with other studies from the Mediterranean, sequence haplotypes and RFLP haplotypes associated with IVS-I-110 allele were noted to be more diverse in Turkish samples compared to that of Lebanese. Zahed et al., 2002 indicated unicentric origin of IVS-I-110 (G>A) and hypothesised the probability of its introduction to Lebanon by migration or settlements from Turkey where it initially emerged. As codon 39 (C>T) was found to be rare in Lebanon, further insights regarding its origin and gene flow were not obtainable.

Morocco

Among 598 children from the Berber population of the Mzab, Merghoub et al. (1997) found Hb C and Hb D-(Ouled Rabah) in the same gene frequency (0.015). Hb D-(Ouled Rabah) is considered a private marker of the Kel Kummer Tuaregs. Haplotype analysis suggested a single origin of the Hb D mutation. Genetic markers calculated from blood group data clustered Mozabites and Tuaregs with the other Berber-speaking groups, Arabic-speaking populations being more distant. However, they found no specific relationship between the Mozabites and Kel Kummers. Tuaregs in general exhibit features that tend to differentiate them from other Berber-speaking groups. Merghoub et al. (1997) concluded that Hb D-(Ouled Rabah) may be specific for Berber-speaking populations and noted that the origin of the Berber people is not clearly established.

Oman

White et al. (1986) analyzed 5000 subjects from three major Peninsular Arab States and determined the frequency of beta thalassemia in Oman to be 2.4%.

In two members of an Arabian family from Oman, Ramachandran et al. (1992) discovered a leu-to-val replacement at position beta-32 by reversed phase high performance liquid chromatography. In one person, it occurred with Hb S and in the other with Hb A. Although Hb Muscat was slightly unstable, its presence had no apparent adverse effect on the health of its carriers.

White et al. (1993) re-estimated the frequency of high HbA2 Beta Thalassemia trait in Omanis to be 0.015.

Rajab et al. (2000) conducted a study to determine the birth prevalence of symptomatic hemoglobinopathies (with exclusion of alpha-thalassemia) in Oman through a national register which was obtained by gathering information (demographic and course of the disease) about the patients from hospital-based registers of all 17 regional hospitals and two tertiary care centers. In total, 781 cases of beta-thalassemia were included, but 548 cases (70%) were excluded after sorting out the duplicates and excluding those with wrong diagnosis. This register was then updated annually and new cases were added thereafter. By December 1995, 243 patients with homozygous beta-thalassemia (233 retrospectively from hospital records and 10 from one year prospective registration) were identified. The majority of beta-thalassemia cases were under the age of 16 years. The birth prevalence of symptomatic beta-globin disorders in Oman was 1 in 323 live births or 3.1 per 1000 live births in 1989-1992, which included 0.4 per 1000 live births of homozygous beta-thalassemia. Each year, it was calculated that 15 new cases of beta-thalassemia were expected to be born and the heterozygotes carrier frequency was 4% according to the national register. The regional distribution of beta-thalassemia revealed that it was more prevalent (more than 70% of cases) in the North Eastern coastal line of Oman in regions with smear-positive rates of malaria of 1% to more than 5% (parts of North Batna, Muscat and South Shargiya).

Al-Riyami et al. (2001) estimated the prevalence of hemoglobinopathies in Oman by interviewing members of households (6600 with response rate of 92.5%) randomly selected from a list prepared from a sample of 264 units chosen from all Oman districts. The 1993 national population census was used as a frame for the two-stage stratified probability sampling. Blood was withdrawn from 6342 children (aged 0-5 years) and analyzed for complete blood count and blood indices, and levels of hemoglobin S, A2 (values more than 3.5% confirmatory of beta-thalassemia trait in the absence of any hemoglobin abnormality) and F. The prevalence of beta-thalassemia trait was 2.2% and the mean level of HbS was 28.8% in 219 children with ages of 2 to 5 years (no regional variation). Beta-thalassemia trait showed significant association with mild anemia (detected in 3.2%) and showed significant regional variation, being more common in North Batinah (3.6%) and Muscat (3.0%), and least common in Dhofar (0.5%) and North Sharqiya (0.9%), but no association with age, gender, or history of blood transfusion (during one year before the study) was detected. The prevalence of first cousin consanguinity was determined as 33.6%, and it was associated significantly with homozygous blood disorders. Upon comparison of the prevalence with that of other countries of the Gulf Cooperation Council (GCC), Oman lay in between, as that of United Arab Emirates was the lowest (1.7%) and Saudi Arabia had the highest prevalence (2.4%). On combing these results with the 1993 census, it was calculated that in Oman, 5392 children under the age of five years had beta thalassemia trait, and according to the authors' results and the Hardy-Weinberg equation, the number of children born yearly with a major hemoglobinopathy was 2 per 1000 live births which increased to 3 per 1000 live births upon correction for consanguinity. Therefore, with a birth rate of 42,000/year, 125 children with a major hemoglobinopathy were calculated to be born yearly. As these numbers would increase the burden on health services, Al-Riyami et al. (2001) suggested that future health planning for Oman should be undertaken by improving and strengthening the national programs for detection, genetic counseling and health education.

Palestine

Zlotogora (1997) conducted a survey of 2000 different Palestinian Arab families. In 601 cases, an autosomal recessive disease was diagnosed or strongly suspected. The distribution of these disorders was not uniform and some disorders, such as Krabbe disease, were found at high frequency in only a small part of the population. For some other disorders, a high prevalence was also reported among Palestinian Arabs living in other regions, for example, beta thalassemia, Bardet-Biedl syndrome, Meckel syndrome, autosomal recessive congenital hydrocephalus, and recessive osteopetrosis.

Qatar

Fawzi et al. (2003) undertook a hospital-based study, in which they studied 1,702 Qatari nationals (905 females and 797 males) referred for investigation on suspicion of a hemoglobinopathy. All patients were subjected to analysis through hemoglobin electrophoresis and full blood count, sickling, and other screening studies. Of these, 16.9% showed a normal electrophoresis pattern, while in another 8.6%, the pattern was considered inconclusive, either due to the presence of iron deficiency anemia or due to a recent blood transfusion. Beta-thalassemia trait was revealed in 28% of the patients, whereas beta-thalassemia intermedia and major were detected in 0.11% and 0.76%, respectively. In addition, 1.53% of the patients were seen to have HbS/beta thalassemia. [Fawzi ZO, Al-Hilali A, Fakhroo N, Al-Bin-Ali A, Al-Mansour S. Distribution of hemoglobinopathies and thalassemias in Qatari nationals seen at Hamad hospital in Qatar. Qatar Med J. 2003; 12(1):20-4.]

In a study by El-Menyar et al. (2006) analyzing data pertaining to all patients less than 50-years of age, who were hospitalized between 1996 and 2003 with cardiomyopathy in Qatar, a rare association was noticed in two patients with comorbidity of dilated cardiomyopathy and thalassemia. The patients were 20 and 21-years old males. Both had reduced ejection fraction (14-21%), and died within 2-years. In the entire group studied, this association was found to have the shortest period between diagnosis and death.

Al-Obaidli et al. (2007) analyzed, for the first time, the molecular basis of beta-thalassemia in Qatar to define the beta-thalassemia mutational spectrum in Qatar. A total of 37 patients constituted the study population, of whom 28 were clinically recognized as transfusion-dependent beta-thalassemia carriers, three were sickle cell disease cases and six were referred for diagnosis of an unexplained microcytic anemia. The reverse dot-blot, denaturing gradient gel electrophoresis (DGGE), direct DNA sequencing technique and PCR-based procedurea were used in this study. Al-Obaidli et al. (2007) found 12 different beta-thalassemia alleles in the Qatari population. The most highly prevalent mutant allele was IVS-I-5 (G to C; a beta-plus type), followed by codons 8/9 (+G; a beta-zero type). They represented 35.4% and 26.1% of the total thalassemia alleles, respectively. Both these prevalent mutant alleles were found in large numbers in the homozygous state, likely due to the high rate of consanguinity in Qatar. The third mutant allele was IVS-II-1 (G to A; beta-zero; 9.2%), followed by 25 bp deletion (beta-zero; 6.2%) and IVS-I-110 (G to A; beta-zero; 6.2%). The other rare mutations found in Qatar were codon 8 (-AA), followed by codon 15 (G to A), codon 44 (-C), codon 30 (G to C), codon 39 (C to T) and IVS-I-1 (G to A). Although the DNA sequencing of the entire beta-globin gene region was performed in two patients with typical thalassemia clinical features and transfuaion dependency, Al-Obaidli et al. (2007) failed to reveal the second mutant alleles in these patients. This led Al-Obaidli et al. (2007) to suggest that mutations likely occurring elsewhere than in the beta-globin gene per se. Al-Obaidli et al. (2007) concluded that the spectrum of beta-thalassemia mutations is quite strikingly wide comparing to the small size of the population in Qatar. Two years later, Al-Obaidli et al. (2009) reported the molecular characterization of one of the two alleles which were remained uncharacterized in a 16-year-old Qatari girl reported earlier by Al-Obaidli et al. (2007). The allele is a novel deletional variant beta-thal allele, hitherto unreported in the literature. This deletion is a deletion of 192 bp within beta-globin gene and it spans 60 bases in exon 1, the entire intron 1 of 130 bases and the first two bases in exon 2, leading to predict that the mutant gene will direct the synthesis of a truncated polypeptide of 21 amino acids instead of the normal 146 amino acids due to a reading frameshift and the premature occurrence of a stop codon. The second mutation in the patient was found to be the IVS-I-5 mutation. Al-Obaidli et al. (2009) thus concluded that the patient is a compound heterozygote for the novel deletion and the IVS-I-5 mutation. Her parents and her similarly affected brother were not available for testing. Al-Obaidli et al. (2009) concluded that the presence of this novel deletional allele in a compound heterozygous state with a non-deletional allele warrant caution in a diagnostic setting, especially in the absence of family study.

Saudi Arabia

Wong et al. (1989) found a T>G change at position -3 in the acceptor splice site of IVS1 (TAG>GAG) in a Saudi Arabian patient.

Sudan

Vella and Hassan (1961) described a Northern Sudanese girl who presented at the age of 12 months with rickets associated with severe hypochromic anemia, aniso-poikilocytosis, and marked splenomegaly. Upon management of rickets, hypersplenism became clearly evident, by the rapid disappearance of transfused RBCs from circulation and thrombocytopenia. The patient's condition improved following splenectomy. Two years later, she was readmitted, complaining of weakness in her right leg. The patient was chronically anemic. Paper electrophoresis of her hemoglobin detected an abnormal amount of fetal hemoglobin, suggesting thalassemia major. A study on her family showed both of her sisters to be hypochromic, with increase in erythrocyte osmotic resistance. The younger sister was pale with a palpable spleen. The parents were first cousins. The mother had thalassemia minor, and peripheral smears for the father showed hypochromia, moderate aniso-poikilocytosis, and microcytosis. The maternal grandmother and two of five siblings of the mother suffered from thalassemia minor. Vella and Hassan (1961) suggested that the lack of reports of beta thalassemia in the Northern Sudanese population is probably due to the disease being obscured by the presence of the prevalent endemic diseases and nutritional disorders.

Prehu et al. (2002) described a heterozygous hemoglobin variant that combined the change of Hb O-Arab and Hb Hamilton on the same beta-globin allele. The other allele carried the Hb S mutation. The patient was a child of Chad-Sudanese descent, suffering from a sickle cell syndrome. Compared to the classic description of the Hb S/Hb O-Arab association, the additional Hb Hamilton mutation did not seem to modify the clinical presentation.

Syria

Noguera et al. (2002) described Hb Agenogi in an Argentinean patient with Syrian and Hungarian ancestry.

Tunisia

Chibani et al. (1988) determined the spectrum of mutations producing beta-thalassemia in Tunisia by direct DNA analysis using hybridization with allele-specific oligonucleotide probes and restriction endonuclease assay. In the 34 unrelated beta-thalassemia patients included in the study, Chibani et al. (1988) identified four previously unreported haplotypes and found that this population differs from others in Mediterranean areas in the frequency of the beta-thalassemia haplotypes, the unexpected observation being the high frequency of haplotype IX. Six different point mutations were found, accounting for 62% of beta-thalassemia genes in this Tunisian population. The molecular defects known to be the most frequent in Mediterranean (nonsense codon 39, IVS1 nt 110, IVS1 nt 6) only make up 37% of the mutant genes. Chibani et al. (1988) also found a splice junction mutant, G to A, at position 1 of IVS2 a Tunisian patient and the splice junction mutant, T to G, at position 2 of IVS1 in another patient.

In a young Arabian boy living in Tunisia, Molchanova et al. (1992) detected a leu48-to-pro substitution, causing Hb Bab-Saadoun, in the beta chain. Since the parents did not have the variant, it presumably occurred by spontaneous mutation. It was thought that the presence of Hb Bab-Saadoun unlikely results in a hemolytic anemia.

In a Tunisian patient with thalassemia intermedia, Jacquette et al. (2004) identified compound heterozygosity for mutations in the HBB gene: a change from AATAAA to AAAAAA in the polyadenylation site of the gene and a 2-bp insertion (25insTA) in codon 9, causing a frameshift with a premature termination at codon 19.

United Arab Emirates

White et al. (1986) analyzed 5000 subjects from three major Peninsular Arab States and determined the frequency of beta thalassemia in the United Arab Emirates to be 1.7%. [Note: data from other studies indicate that the actual frequency of beta-thalassemia in the UAE is higher than 8%; see below > Baysal, 2001].

Miller et al. (2003) carried out a cross-sectional community clinic-based capillary blood survey to produce a hematological profile of preschool national children of the United Arab Emirates. The sample included 1-5-year-old Emirati children attending a Primary Health Care Center in Al-Ain from April 2000 to October 2000. Those children with capillary hemoglobin (Hb) and mean corpuscular volume (MCV) values below predetermined cutoffs were offered venous blood hematological workup. A random sample of children with values above those cutoffs was also offered the same workup. In total, 496 children were surveyed. The mean Hb and adjusted MCV rose with increasing age but were not significantly different by gender. Two hundred and sixty-two children with Hb or MCV below the cutoffs and 50 children above the cutoffs were venous blood tested. The estimated abnormalities for this population of children were as follows: anemia 36%; iron deficiency anemia 10%; glucose-6-phosphate dehydrogenase (G6PD) deficiency 9%; sickle cell trait 5%; and beta thalassemia 9%.

In an update on the status of beta-thalassemia in the UAE population, Dr. Erol Baysal (personal communication, April 2006) indicated that 51 beta-thalassemia mutations are found in 372 beta-thalassemia patients, nationals of the UAE. About two-thirds of the patients were homozygotes, and half of these were homozygous for the Arabian Indian IVS-I-5 (G-C) mutation.

Yemen

White et al. (1986) analyzed 5000 subjects from three major Peninsular Arab States and determined the frequency of beta thalassemia in Yemen to be 6.24%.

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