RARE AND NEW MUTATIONS
OF Β-GLOBIN IN AZARI POPULATION OF IRAN,
A CONSIDERABLE DIVERSITY
Abbasali F.H.1, Mahmoud K.Sh.2,3, Hengameh N.3, Mina D.H.3, Setare D.3, Hale D. M3, Sima D.M.2,3*
*Corresponding Author: MD.PhD Sima Mansoori Derakhshan, Department of Medical Genetics, Faculty
of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran, & Ebne Sina Medical Genetics Laboratory,
Specialized and Sub-specialized Outpatient Clinics, Tabriz
page: 51
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DISCUSSION
Northwest Iran consists of three provinces, East - and
West -Azerbaijan, and Ardebil. This area is located on
the border with Iraq, Turkey, Armenia, the Republic of
Azerbaijan, and the Nakhichevan enclave. Azeri Turkish
people account for most of the population, but Kurds and
other minorities are also scattered throughout the region.
Regarding the variation in the mutation frequencies in
different parts of Iran, it can be stated that the existence
of different ethnicities, such as Fars, Azeri, Kurd, Baluch,
and Lur could be the most possible reason. On the other
hand, historically, a variety of the mutations have been
introduced to Iran as a consequence of years of wars, invasions,
and massive migrations.
In Iran, the prevalence rate of β-thalassemia carriers
is about 4%, while in northwest of Iran, it is half the
country’s average rate (less than 2%) (20).
With the development of molecular techniques, the
discovery rate of common mutations has increased remarkably.
Over the past two decades, ARMS-PCR has been used
as the main technique for diagnosing known mutations (21),
however, this method cannot detect all the unknown mutations.
Inconclusive results obtained in approximately 20% ARMSPCR
necessitated the use of additional methods, such as
sequencing, Gap–PCR, and MLPA techniques.
More than 200 mutations of the β-globin gene have
been recognized globally, primarily categorized as point
mutations (9). The prevalence of mutations differs according
to race and ethnicity, and in each geographical area,
several mutations are more prevalent than the others.
Codon 39 C>T mutation has been found in 95.7%
of Sardinian patients and 25% of the patients with
β-thalassemia major in Saudi Arabia (22, 23). However,
this mutation is found only in 2.5% of patients with -thalassemia
in Iran (18). Similarly, CD41-42 (-CTTT) mutation
is rare in Iran, however, it is most common (45.81%) in
China (Guangxi) (24) . Some rare or unknown mutations
have been found among the β-thalassemia cases, and their
identification can improve the quality of screening protocols
for precise detection of the carriers and rapid detection
of the fetuses affected with β-thalassemia major.
Table 1 and Figure 5 summarize the findings of the
current study and compare them with the data obtained from
the reports published from the Northern, Central, and Southwestern
regions of the country, as well as two larger general
studies. Furthermore, it shows the frequencies reported by
the neighboring countries including Turkey (25), Iraq (26),
the Republic of Azerbaijan (27, 28), and Pakistan (29).
Derakhshandeh-Peykar et al. surveyed the presence
of β-globin gene mutations among 394 heterozygote β-thalassemia cases using the ARMS-PCR and DNA sequencing
methods, in the northern Caspian Sea provinces of
Gilan, Mazandaran, and Golestan. They identified 19 mutations,
with IVS-II-1 (G>A) being the most frequent (51.6%).
Table 1 shows 14 rare mutations found in their study.(30)
Galehdari et al. (2010) studied 1241 cases in the
southwest of Iran and reported 14 rare mutations partially
compatible with the current findings (Table 1) (31).
CD36/37(-T) and IVS-I 3end (-25bp del) mutations were
considered to be rare in our study and accounted for 14
and 5.6% of β-globin gene mutations in this geographic
region, respectively.
Najmabadi et al. (4) and Nejat Mahdieh et al. (34)
conducted relatively comprehensive studies on the rare
mutations in Iran as a whole. In contrast to the current
findings, Najmabadi et al. showed that CD36/37(-T) and
Hb Lepore had frequencies of more than 2% (5.52 and
9.8%, respectively) and were considered as the common
mutations.
Nejat Mahdieh et al. (34) reviewed 32 published studies
conducted in Iran on the 31734 β-thalassemia cases and
reported lower frequencies of IVS-I-130(14.63%), CD16
(-C) (9.31%), CD82/8 (-G) (11.97%), CD41/42 (-CTTT)
(5.32%), and IVS-I-128 (5.32%) mutations compared to
our findings.
Sicilian (-13,337bp) deletion was the most frequent
rare mutation in our study, accounting for 30 out of 1541
alleles (2.01%). Esteghamat et al. reviewed the deletional
mutations in β-thalassemia, and reported a frequency of
about 1.26% for the Sicilian (-13,337bp) deletion in 1500
independent cases in Iran (33). As reflected by its name,
this deletion is originated from the Mediterranean region,
especially Italy and Greece.
Codon 36/37 (−T) is the most frequent mutation (31-
34%) in Lur and Bakhtiari, two Iranian minority ethnic
groups living in the central parts of Iran (7). Galehdari et al.
(35) and Derakhshandeh-Peykar et al. (32), in their studies
in the southwestern and central parts of Iran, reported a frequency
of 22.70 and 19.7% for this mutation, respectively.
In the present study, this mutation was found in 1.94% of
the independent individuals. This mutation has been rarely
reported in the neighboring countries of Turkey (25), Iraq,
and the Republic of Azerbaijan (34). It has been reported
with a frequency of 0.5- 1.5% in Saudi Arabia (23). While
it has been found to come from the Kurdish population
of Iran (36), it is most commonly found in Khuzestan
and Lorestan provinces. Increase in its frequency in these
subpopulations could be due to gene flow and genetic drift.
CD15(G>A) mutation with Asian-Indian origin has
been previously reported in Iran with low frequency, ranging
from 2.1-3.9% (34). Yet, in our study, its frequency
was equal to 1.4%. This mutation has been reported in
Pakistan with a frequency higher than in Iran. In Pakistan,
this mutation has a decreasing frequency from east to west;
therefore, a lower frequency of this mutation is expected
in northwest of Iran (1.4%) compared to Iran’s general
statistics (3.99%).
The CAP+22 (G>A) mutation of Mediterranean/Bulgarian
origin was found in this study with a frequency of
0.53 % in eight out of 1541 analyzed subjects. Akhavan-
Niaki et al. (10) screened for β-globin gene mutations
among 1635 Iranian carriers in the north of Iran, and found
that the CAP+22 (G>A) was the least frequent mutation,
identified in 0.10% of the cases. This mutation has been
reported very rarely (0.04%) in Iran and has been mainly
detected in Azeri populations in other surveys.(25, 37)
CD25/26, which originally is a Tunisian mutation, is
among the rarest mutations in Iran. It was introduced by
Haghi et al. in 2009 in Tabriz, East Azerbaijan province,
Iran (13). In this study, this mutation was identified in five
out of 1541 subjects (0.33%).
The CD16 (-C) β0 mutation of Asian-Indian origin
is a rare mutation with a frequency of 0.9% in Isfahan
province (Central Iran) (32) and had a frequency of 0.13
% in our study.
Roudkanar et al. (38), Najmabadi et al. (37), and
Rahim et al. (39) described the IVSI-130 (G>C) mutation
of Middle Eastern origin (36) as the most common rare
mutation in Iran with 4, 11, and 1 alleles, respectively.
Yavarian reported a frequency of 0.41% for this mutation
in Southern Iran (40). Similarly, in the present study, this
mutation was observed in 0.35% of the cases (7 alleles).
Ayçiçek et al. reported this mutation with a frequency of
3.5% in Turkey (41). This mutation has been reported
with a frequency of 4.3% in the eastern provinces of Saudi
Arabia (23).
In central Iran, IVSI 3’end 25 del mutation accounts
for about 5% of mutations in the β-globin gene. It is also
frequent in Bahrain and Saudi Arabia with frequencies
of 36 and 14%, respectively (42) . Although this mutation
has been proposed to have an Asian-Indian origin,
southern Iran, particularly the Persian Gulf area, has also
been proposed as the actual place of origin for this mutation
(7, 42). The frequency of this mutation is equal to
1.2% in Northern Iran (30), and has a descending trend
of frequency from the south to the north in Iran. In our
research, this mutation was found in 11 subjects (0.71%).
A study on patients with thalassemia in Northeastern
Iran in 2018 (43) showed that the frequency of CD 29
(GGC>GGT) was seven in 100 cases (7%), but in the current
study, its frequency was reported to be five (0.32%).
The CD30 (AGG>AGC) mutation has a nearly 2%
frequency in Iran (7, 34). In the current study, its frequency
was equal to 0.52 %. HBBP1 and up HBB-0.5Kb down HBB CD69
G>A (HBB: c.208G>A) (2 cases), c.*96T>C (2 cases),
HBB:c.*74(A>G) (4cases), (-86) C>G (3cases), (-87) C>T
(5cases), and IVS-II-772 (G>A) mutations/variants were
reported for the first time in Iran (Figure 4).
In accordance with our findings, it has been previously
reported that the CD69G>A(HBB: c.208G>A), Hb
City of Hope is a rare and silent Hb variant. Hemoglobin
electrophoresis cannot separate it from Hb A (44).
CD69G>A appears to have no obvious functional effects
on the β-globin chain properties in the heterozygotes, as
do two other β variants at codon 69, Hb Kenitra and Hb J
Cambridge (45, 46). But it has been reported that the compound
heterozygote for this variant and β-globin mutations
result in the development of β-thalassemia .(47)
In our study, the phenotype of the heterozygote cases
for CAP + 1570 T > C (HBB:c.*96T > C) mutation was
compatible with the silent carrier of β-thalassemia. This
variant was reported previously by Vinciguerra et al.
in 2015 (48) showing variable phenotype ranging from
β-thalassemia carrier to mild form of β-thalassemia intermedia
in the compound heterozygotes for this mutation
and severe β-globin mutations. These findings allow us to
better understand the clinical implications of this variant
that can be categorized as a silent β-thalassemia defect.
Regarding phenotype of the heterozygote cases for
CAP+1548 A>G (HBB:c.*74 A>G), it can be said that this
variant might have decreased the MCV by 76 on average
and also the MCH to 23.3 without elevation in the HbA2
level. As the iron deficiency in the population under study
had been primarily excluded by the appropriate means
and α-globin genes mutations were ruled out by the Gap-
PCR and sequencing, lower hematological indices could
be attributed to this variant. Therefore, according to these
findings, it cannot be strongly concluded that this variant
can be categorized as a β++ mutation.
The phenotype of the heterozygote cases for the IVSII-
772 mutation was found to be β++. As these cases had
the α3.7deletion in α-globin locus, in addition to this variant,
the effect on the phenotype could not be concluded
precisely. Consequently, the clinical significance of this
variant remains unknown.
Although, CD126 GTG>GGG mutation (Hb Neapolis)
was detected in only 0.13% of the studied population,
reporting of this variant is important due to the fact that the
heterozygote cases for this variant and β0 mutations have
previously shown typical characteristics of the thalassemia
intermedia (49).
In the current study, some common mutations which
were missed by the routine ARMS-PCR technique, were
rediscovered by the sequencing technique demonstrating
the inferior sensitivity of ARMS- PCR in comparison
with more modern methods. This limitation should be
considered for any molecular laboratory test involved in
the β-thalassemia PND program.
Two cases remained unidentified, despite all efforts.
There are various types of mutation in the β-globin locus
influencing the gene action at any level of transcription,
through translation, for example, mutation in the locus
control region (LCR) or other regulatory regions can lead
to β- thalassemia or β-hemoglobinopathy (50). Modern
methods for molecular analysis, such as next generation
sequencing (NGS), may be fruitful in these conditions.
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