Hemoglobin, 35(5–6):581–588, (2011)

Copyright © Informa Healthcare USA, Inc.

ISSN: 0363-0269 print/1532-432X online
DOI: 10.3109/03630269.2011.634706

PRESENTED AT THE INTERNATIONAL CONFERENCE ON

HEMOGLOBIN DISORDERS, KUWAIT, February 5–7th, 2011

MOLECULAR BASIS OF β-THALASSEMIA IN THE UNITED ARAB

EMIRATES

Erol Baysal
Pathology and Genetics Department, Dubai Genetic and Thalassemia Center, Dubai Health Authority,
United Arab Emirates

! In an attempt to define the prevalence of β-thalassemia (β-thal) in the United Arab Emirates
(UAE), we have conducted molecular studies on nearly 2000 randomly-selected adult UAE nation-
als. The results demonstrated that the prevalence of β-globin gene defects in the UAE was 8.5%.
Among these anomalies were β-thal mutations, abnormal hemoglobin (Hb) variants, e.g., Hb S,
Hb D-Punjab, Hb O-Arab, Hb C and Hb E. The sickle gene (βS or Hb S) contributed significantly
to the molecular epidemiology of the hemoglobinopathies in the UAE. In this article, Hb S and other
abnormal Hbs are excluded as they are comprehensively described by other contributors in this current
issue.
The molecular characterization and mutational analyses of all β-thal patients were car-
ried out using current molecular techniques including amplification refractory mutation system
(ARMS), restriction enzyme analysis (REA), dot-blot hybridization, β-strip hybridization, allele-
specific oligonucleotide (ASO), polymerase chain reaction (PCR), gap-PCR and DNA Sequencing.
Most of these techniques are now virtually obsolete. Almost all molecular characterizations are cur-
rently performed through PCR followed by DNA sequencing using a fully automated ABI PRISMTM
3130 Genetic Analyzer.
Our molecular studies showed that the majority of the β-thal mutations in the UAE are very
severe; the most common allele was the IVS-I-5 (G>C). Although this allele is a β+ -thal, its pheno-
type is very severe. All other mutations are also severe β0 -thal. High frequency of moderate or severe
β-thal mutations have implications in the wide spectrum of clinical manifestations seen in patients
whose phenotypes vary from β-thal intermedia (β-TI) to severe transfusion-dependent β-thal major
(β-TM).

Received 9 September 2011; Accepted 9 September 2011.

Address correspondence to Erol Baysal, Ph.D., F.R.C.P. (London), Consultant & Head of Mole-
cular Genetics, Senior Lecturer, Pathology and Genetics Department, Dubai Genetic and Thalassemia
Center, Dubai Health Authority, United Arab Emirates; Tel.: +9714-219-3453; Fax: +9714-311-3247;
E-mail: ebaysal@dha.gov.ae

581
582 E. Baysal

The molecular pathology of the β-thal patients demonstrated that a vast majority were homozy-
gous. The most frequent homozygous mutation was the IVS-I-5(G>C)/IVS-I-5(G>C) (53.0%)
followed by –25 bp del/–25 bp del (6.8%), codons 8/9(+G)/codons 8/9(+G) (2.8%) and codon
39(C>T)/codon 39(C>T) (2.4%). Four mutations accounted for 65.0% of the homozygous
patient population. Remarkably, the two most prevalent mutations, IVS-I-5 and Hb S, accounted
for 77% of all the homozygous β-thal patients from the UAE. We showed 13 discrete homozygosities
in the UAE national patients in contrast to 23 homozygosities in the expatriate population. Since
the number of homozygous mutations has a direct correlation with the degree of consanguinity, the
data shown here corroborate the social tendency towards family planning. In fact, in the UAE,
more than 50% of all marriages are between relatives and more than half of these are between first
cousins.

Keywords Hemoglobinopathies, β-Thalassemia (β-thal) mutations, United Arab

Emirates (UAE), Consanguinity

INTRODUCTION
The United Arab Emirates (UAE) is a federation of seven emirates situ-
ated on the Eastern Arabian Peninsula bordering Oman, Saudi Arabia and
Qatar. Iran and the Arabian Gulf are in the north. The population of the
UAE is diverse and, like the other Gulf countries, is made up of immi-
grants from the Middle East, Africa, India, Pakistan, Iran, Southeast Asia
and Europe. In the last two decades, the population of the UAE swelled sig-
nificantly from 600,000 in 1985, to 2.5 million in 1995, and boasts slightly
over 4 million people today (estimated at 4.04 million in July 2005). Life
expectancy is one of the highest in the world; 72.7 years for males and 77.9
for females (1).
Dubai is the most populous emirate in the UAE with an estimated
1.4 million inhabitants (ca. 2005). The oil revenues in the late 1960s led
to a rapid economic development that transformed Dubai into a modern
metropolis. Today, Dubai is the undisputed commercial and business hub in
the entire Gulf Region. The UAE nationals make up approximately 19% of
the total population, while South Asians (Indians and Pakistanis) make up
50%, Arabs and Iranians 23%, and Westerners and Southeast Asians account
for 8%. Around 80% of the population is comprised of expatriates.
β-Thalassemia (β-thal) constitutes a major public health problem in
the UAE. Not much was known about the spectrum of β-thal mutations
in the UAE until the mid-1990s. Preliminary surveys by White et al. (2,3)
showed that β-thal and Hb S/β-thal and other abnormal hemoglobins (Hbs)
existed in the UAE at high frequencies. Owing to the unavailability of DNA
methods, the findings were limited to hematological evaluations such as
microcytosis, hypochromia, iron status, and Hb A2 values. Due to the large
family sizes and the lack of preventive programs previously, the majority of
families have more than one affected child.
 Molecular Basis of β-Thalassemia in the UAE 583

The Dubai Genetic and Thalassemia Center was inaugurated in

1995. Since then the Molecular Genetics Unit has been actively involved
in the identification, characterization and elucidation of all types of
hemoglobinopathies, predominantly in Dubai. During 1995–2007, a total
of 838 patients were characterized at the molecular level.
Previous hematology-based surveys showed that the UAE exhibited one
of the highest carrier frequencies of β-thal in the Gulf region (2–6). The
first molecular study on the distribution of β-thal in the UAE was reported
by Quaife et al. (6) who showed seven β-thal alleles in 50 traits with the most
common allele being the IVS-I-5 (G>C) substitution. It was suggested that
this mutation was introduced to the UAE by population migration from the
Baluchistan province of Pakistan, which neighbors Iran and Afghanistan.
Our initial study involved 2,000 randomly-selected adult UAE nation-
als. The results demonstrated that the incidence of β-globin gene defects
in the UAE was 8.5% (7,8). The molecular characterization and mutational
analyses of all β-thal patients were carried out using current molecular tech-
niques including amplification refractory mutation system (ARMS), non
isotopic dot-blot hybridization, restriction enzyme analysis (REA), reverse
dot-blot hybridization, β-strip hybridization, allele-specific oligonucleotide
(ASO) hybridization, direct polymerase chain reaction (PCR), gap-PCR,
manual and automated DNA sequencing. All of these techniques have been
described previously (8,9). The previous hematological analyses included
isoelectric focusing (IEF) and quantitation of Hb types by column chro-
matography. The current investigations used highly sophisticated high
performance liquid chromatography (HPLC) and DNA sequencing.
Molecular studies began with DNA extraction according to the com-
′
monly used procedures. The 5 β segment of the β-globin gene was amplified
′
using a forward primer, located in the upstream promoter region 5 to the
Cap site, and a reverse primer in the second intervening sequence. A vast
′
majority of the β-thal mutations in the UAE were found in the 5 β segment of
′
the β-globin gene. The 3 β segment was only amplified whenever mutation
′
screening of the 5 β revealed no mutation.
One of the most significant observations derived from our molecular
studies is that the majority of the β-thal mutations in the UAE are very severe;
except for the most common allele, the IVS-I-5 (G>C). Although this is a
β+ -thal, all other mutations are severe β0 -thal types. High frequency of mod-
erate or severe β-thal mutations have implications in the wide spectrum of
clinical manifestations seen in patients whose phenotypes vary from β-thal
intermedia (β-TI) to severe, transfusion-dependent β-thal major (β-TM).
In this report we describe the molecular pathology of 838 patients,
of which 412 are UAE nationals and 249 of these were homozygous.
Table 1 [modified from (10)] shows the distribution of β-thal mutations
in 188 homozygous patients (excluding all the abnormal Hbs). The most
584 E. Baysal

TABLE 1 Homozygous β-Thalassemia in the United Arab Emirates National Patients

[modified from (10)]

Number of Frequency
Mutation n Chromosomes (%)a

1 IVS-I-5(G>C)/IVS-I-5(G>C) 132 264 53.0

2 –25 bp del/–25 bp del 17 34 6.8
3 Codons 8/9(+G)/codons 8/9(+G) 7 14 2.8
4 Codon 39(C>T)/codon 39 (C>T) 6 12 2.4
5 Codon 30(G>C)/codon 30(G>C) 5 10 2.0
6 IVS-II-1(G>A)/IVS-II-1(G>A) 4 8 1.6
7 Codon 5(–CT)/codon 5(–CT) 4 8 1.6
8 –88(C>A)/–88(C>A) 3 6 1.2
9 IVS-I-1(G>A)/IVS-I-1(G>A) 3 6 1.2
10 Codon 15(G>A)/codon 15(G>A) 2 4 0.8
11 Codon 8(–AA)/codon 8(–AA) 2 4 0.8
12 IVS-I-110(G>A)/IVS-I-110(G>A) 2 4 0.8
13 Codons 82/83(–G)/codons 1 2 0.4
82/83(–G)
TOTAL 188 376
a Excluded from the table are Hb SS (23.7%) and Hb DD (0.8%).

frequent homozygosity was the IVS-I-5/IVS-I-5 (53.0%) followed by –25 bp

del/–25 bp del (6.8%), codons 8/9(+G)/codons 8/9(+G) (2.8%) and
codon 39(C>T)/codon 39(C>T) (2.4%). These four mutations account for
65.0% of the homozygous patient population. Also depicted in Table 1 are
13 discrete homozygosities discovered in our UAE national patients in con-
trast to 23 homozygous mutations in the expatriate population. Since the
number of homozygous mutations has a direct correlation with the degree
of consanguinity, the data shown here corroborate that more than 50% of
all marriages in the UAE are between relatives, and more than half of these
are between first cousins.
Table 2 lists the relative frequencies of the 25 different mutations found
in the UAE national patients (n = 412). The first 10 mutations account
for 71.1% of the total β-thal chromosomes (excluding Hb S which occurs
at 21.1%). Table 2 represents the entire β-thal patient population; homozy-
gotes and compound heterozygotes. The most frequent mutation was the
IVS-I-5 at 44.5%. This is perhaps one of the highest incidences of the IVS-I-5
allele reported worldwide so far. This was followed by the –25 bp del allele
at 8.6%.
The β-thal mutations in the UAE nationals showed considerable hetero-
geneity, similar to that found in the expatriate population. A total of 53
different compound heterozygotes were observed (data not shown). The
most prevalent compound heterozygotes were the βS /IVS-I-5 (31 patients),
IVS-I-5/–25 bp del (17 patients) followed by IVS-I-5/IVS-I-6(T>C) and IVS-
I-5/codon 8 (–AA) (10 patients each). Some of the mutations were rare and
 Molecular Basis of β-Thalassemia in the UAE 585

TABLE 2 β-Thalassemia Gene Frequency Among the United Arab Emirates National
Patients (n = 412; 824 April 2007) [modified from (10)]

Gene
Number of Frequency
Mutation Chromosomes (%)a

1 IVS-I-5 (G>C) 367 44.5

2 –25 bp deletion 71 8.6
3 Codons 8/9 (+G) 25 3.0
4 IVS-II-1 (G>A) 23 2.8
5 Codon 39 (C>T) 18 2.2
6 Codon 8 (–AA) 18 2.2
7 Hb D-Punjab (GAA>CAA) 18 2.2
8 Codon 30 (G>C) 17 2.1
9 Codon 5 (–CT) 17 2.1
10 IVS-I-6 (T>C) 12 1.5
11 –88 (C>A) 9 1.1
12 Codons 82/83 (–G) 8 1.0
13 IVS-I-110 (G>A) 8 1.0
14 IVS-I-5 (G>T) 7 0.9
15 Codon 15 (G>A) 7 0.9
16 Codon 44 (–C) 6 0.7
17 Codon 110 (T>C) 3 0.4
18 IVS-II-848 (C>A) 3 0.4
19 PolyA site (AATAAA>AATAAG) 3 0.4
20 –101 (C>T) 2 0.2
21 Hb Knossos (codon 27, G>T) 1 0.1
22 Codon 37 (G>A) 1 0.1
23 Codons 36/37 (–T) 1 0.1
24 Hb E (codon 26, G>A) 1 0.1
25 δβ deletion 1 0.1
a Excluded from the table is Hb S (21.1%).

some were observed only once. It is important to note that for both the
homozygous and compound heterozygous patients, all the mutations were
of the β0 -thal type except for the β+ -thal IVS-I-5 (G>C)mutation. However,
the latter has a very severe phenotype in the homozygous state or when
associated with another β0 allele. This is because only 5% Hb A mRNA is
processed through the mutant IVS-I-5 chromosome, a level insufficient to
alleviate severe β-globin chain deficiency.
During the last decade, our center conducted molecular characteriza-
tions of 426 expatriate β-thal patients. Of these, 256 were homozygous and
171 compound heterozygotes. The number of expatriate patients in our reg-
istry was essentially equal to that of the UAE nationals; 426 expatriates and
412 UAE nationals; 50.8 and 49.2%, respectively (Figure 1). The majority
of the expatriate patients were from Pakistan (28.3%), Oman (23.0%), Iran
(18.5%) and India (8.9%). In the expatriate patients, a total of 78 different
combinations of compound heterozygote mutations were defined (data not
586 E. Baysal

450
412
400

350

300

250

200

150
121
98
100
79
38
50
15 14 10 8 8 6 5 4 3 2 2 2 1 1 1 1 1 6
0
UAE
PAK
OMA
IRAN
INDI
JOR
BAN

EGY
PAL
BAH
TAN
SYR
KUW
SUD
YEM
LEB
NIGE
PHIL
AFG
AZE
SAU
NON
IRAQ
A

EST

ANO

RBA
DAN

ZAN
IA
ISTA

PT

AN

HAN

DI
GLA

RAIN

EN

E
LIPP
N

AIT

RIA
INE

IA

IJAN
N
DES

ISTA
N

INES
H

N
FIGURE 1 Distribution of UAE national (412) and expatriate (426) β-thalassemia patients.

shown). This was considerably large compared to 53 compound heterozy-

gotes in the UAE nationals. The combined UAE national and expatriate
data makes the UAE by far the most heterogeneous β-thal population in the
world.
Table 3 shows similarities in the distribution of β-thal chromosomes
in the UAE national patients and expatriates. The data show remarkable
resemblance in the number of homozygotes, compound heterozygotes, and
frequency of the most common mutation (IVS-I-5) in the two populations,
thus reflecting significant overlap of family planning, religious, cultural,
traditional and historical values.
Our molecular studies revealed 55 different β-thalassemia mutations
to date in the UAE population as a whole (Figure 2). In simple perspec-
tive, the total number of mutations in the UAE surpasses the combined
number of mutations reported from China and India. These are the two
most populous nations with combined populations exceeding 2 billion, but
the total number of reported mutations hardly exceeds 40. Considering
Dubai’s population of 2 million, one thousandth of the above populations,
 Molecular Basis of β-Thalassemia in the UAE 587

TABLE 3 Comparative Data Showing the Distribution of β-Thalassemia Mutations

Between United Arab Emirates National and Expatriate Patients [modified from
(10)]

Patientsa UAE Expatriates

n 412 426

Homozygotes 249 60.0% 264 62.0%

Compound heterozygotes 163 40.0% 162 38.0%
IVS-I-5(G>C)/IVS-I-5(G>C) 132 54.0% 130 49.2%
(in all homozygotes)
IVS-I-5(G>C)/IVS-I-5(G>C) 132 32.0% 130 31.0%
(in all patients)
IVS-I-5 (G>C) chromosomes 367 44.5% 336 39.4%
Homozygous mutations 15 23
Compound heterozygous 53 78
mutations
a Hb S patients are excluded.

UAE 55
E. Europe 2
S.E ASIA 4
ITALY
N & S AMERICA
TURKEY 2
N. AFRICA 3
ISRAEL
W. EUROPE
JAPAN / 7
GREECE 2
PAKISTAN
INDIA
CHINA 3
IRAN 2
LEBANON
CYPRUS GR
CYPRUS TR 2
0 10 20 30 40 50 60

FIGURE 2 Heterogeneity of β-thalassemia mutations worldwide as measured by the total number of

alleles in a given country or region.

the data reported here reflects the considerably diverse molecular hetero-
geneity in the UAE. However, it must be noted that the genetic diversity of
this scale poses enormous problems in designing prevention programs and
offers frightening prospects to all of us who are engaged in prenatal diag-
nosis programs for β-thal in the UAE. However, this problem is generally
588 E. Baysal

circumvented by carrying out mutational studies on prospective family mem-

bers and creating a comprehensive database prior to performing molecular
analysis.

ACKNOWLEDGMENTS
The author thanks Dr. Mahmoud Taleb, Head of the Genetics Center (Genet-
ics Department, Dubai Health Authority, United Arab Emirates) and the technical
staff for the diagnostic laboratory studies. Special thanks go to Dr. Khawla Belhoul,
Director, and all the colleagues at the Thalassemia Center (Dubai Health Authority,
United Arab Emirates).
Declaration of Interest: The author reports no conflicts of interest. The author
alone is responsible for the content and writing of this article.

REFERENCES
1. Al Hosani H. Health for all in the United Arab Emirates. East Mediterr Health J. 2000;6(4):838–840.
2. White JM, Byrne M, Richards R, et al. Thalassaemia genes in Peninsular Arabs. Br J Haematol.
1985;60(2):269–278.
3. White JM, Byrne M, Richards R, Buchanan T, Katsoulis E, Weerasingh K. Red cell genetic abnor-
malities in Peninsular Arabs: sickle haemoglobin, G6PD deficiency, and α and β thalassaemia. J Med
Genet. 1986;23(3):245–251.
4. al-Gazali LI, Bener A, Abdulrazzaq YM, Micallef R, al-Khayat AI, Gaber T. Consanguineous
marriages in the United Arab Emirates. J Biosoc Sci. 1997;29(4):491–497.
5. El Hazmi MA, Al-Swailem AR, Warsy AS. Molecular defects in β thalassaemias in the population of
Saudi Arabia. Hum Hered. 1995;45(5):278–285.
6. Quaife R, al Gazali L, Abbas S, et al. The spectrum of β-thalassemia mutations in the UAE national
population. J Med Genet. 1994;31(1):59–61.
7. Baysal E. Advances in Hemoglobinopathies Research – Hemoglobinopathies in the United Arab
Emirates. Hemoglobin. 2001;25(2):247–253.
8. Baysal E. Molecular heterogeneity of β-thalassemia in the United Arab Emirates. Community Genet.
2005;8(1):35–39.
9. El Kalla S, Baysal E. Genotype-phenotype correlation of sickle cell disease in the United Arab
Emirates. Pediatr Hematol Oncol. 1998;15(3):237–242.
10. Baysal E, Yousef I, Zeinali M, et al. Molecular basis of hemoglobinopathies in the UAE: implications
for prenatal diagnosis and prevention programs. Emirates Med J. 2007;25(1):7–21.
Copyright of Hemoglobin is the property of Taylor & Francis Ltd and its content may not be copied or emailed
to multiple sites or posted to a listserv without the copyright holder's express written permission. However,
users may print, download, or email articles for individual use.