Accepted Manuscript

New trend in the epidemiology of thalassaemia

Chi-Kong LI, MBBS, MD, FRCPCH

PII: S1521-6934(16)30121-3

DOI: 10.1016/j.bpobgyn.2016.10.013

Reference: YBEOG 1666

To appear in: Best Practice & Research Clinical Obstetrics & Gynaecology

Received Date: 2 May 2016

Revised Date: 21 August 2016

Accepted Date: 14 October 2016

Please cite this article as: LI C-K, New trend in the epidemiology of thalassaemia, Best Practice &Research Clinical Obstetrics & Gynaecology (2016), doi: 10.1016/j.bpobgyn.2016.10.013.

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Title Page

“New trend in the epidemiology of thalassaemia”

Chi-Kong LI,

MBBS, MD, FRCPCH

Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales

Hospital, Shatin, Hong Kong.

Tel: 852-26321019

Fax: 852-26497859

Email: ckli@cuhk.edu.hk

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Abstract

Thalassaemia is the most common monogenetic disorder worldwide. It is common in

areas prevalent with malaria as thalassaemia red cells provide immunity against the

parasite. The incidence of thalassaemia carriers is high in the regions spreading from

Mediterranean, Middle East, India Subcontinent, Southeast Asia to South China. In

the past few decades, migrants from the thalassaemia prevalent countries to

non-prevalent countries, mainly North America and Central and North Europe, are

rapidly increasing in number. The thalassaemia non-prevalent countries may not have

established prenatal screening system for thalassaemia. The genetic subtypes among

the different ethnic groups vary which may pose challenges in prenatal diagnosis.

Genetic counselling on the postnatal course of thalassaemia may be affected by the

genotype-phenotype correlation and co-inheritance of other genetic diseases. New

treatment improves the survival of thalassaemia major patient but some late

complications are only discovered recently with longer survival.

Key words:

Thalassaemia, mutations, prenatal screening, epidemiology.

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Background

Thalassaemia is the most common monogenetic disorder worldwide. About 20% of

world population carries α+ thalassaemia and 5.2% of population is carrying a

significant variant of haemoglobin disorder including β thalassaemia and α0

thalassaemia [1]. Carriers of thalassaemia genes are protected from falciparum

malaria and it is common in countries from Mediterranean region to the east,

including Middle East, India Subcontinent, Southeast Asia and South China [2]. Each

year there are about 56,000 babies born with a major thalassaemia. Majority of the

major thalassaemia requires regular blood transfusion and also iron chelation therapy

[3]. Though the survival of thalassaemia major is improving and most survive beyond

adulthood, the quality of life and ultimate life expectancy is still suboptimal [3, 4].

The financial burden to the family and the community is significant for the expensive

life-long treatment. Prevention programme of thalassaemia major in endemic areas

has been shown to be successful such as in Cyprus and Sardinia [5]. A successful

prevention programme requires efforts from government policy, public education,

genetic counselling, prenatal screening and diagnosis [6]. In the recent few decades

people mobility and migration to other countries is rapidly increasing, the

non-prevalent countries for thalassaemia is now facing the problem of increasing

number of babies born with thalassaemia major [7,8]. The health care workers in the

non-prevalent countries have to get prepared for the prevention and management of

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the ‘new’ diseases.

1 Genetics of thalassaemia

1.1 Alpha thalassaemia

Thalassaemia is due to mutation or deletion of the alpha or beta globin genes

which leads to reduction or total absence of globin chain production. Alpha

thalassaemia gene is located at the chromosome 16 with two alpha globin genes,

α 1 and α 2. About 90% of the mutation is due to deletional type, deletion of one

(-α) or both (- -) α-globin genes from the chromosome [9]. If only one of the 4

alleles is mutated or deleted, α+ carrier, the individual is asymptomatic and the red

cell indexes are usually normal. α+ thalassaemia is actually the most common

thalassaemia mutation in the world. Heterozygous or double heterozygous α+

thalassaemia will not pose significant health burden to the community as the

children born to these carriers are α+ thalassaemia or double heterozygous α+

without severe anaemia. If two of the alpha genes on the same chromosome are

mutated or deleted, there will be total absence of alpha globin production from

that chromosome, called α0 thalassaemia. The carrier of α0 thalassaemia,

thalassaemia trait, has microcytosis of red cells and may have mild anaemia,

however most of them are asymptomatic and only being detected on routine blood

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test investigations.α0 thalassaemia is common in some parts of the world, such

as --SEA deletion of the two alpha genes in Southeast Asia and South China [10].

The double gene deletion, --MED is prevalent in Mediterranean region such as

Cyprus, whereas -- FIL is seen in Philippines. The significance of α0 thalassaemia

is the offspring having 25% chance of being Hb Bart’s hydrops foetalis syndrome,

or alpha thalassaemia major, if both couples are α0 thalassaemia carriers [11]. Hb

Bart’s syndrome is characterized by foetal onset of generalized oedema, pleural

and pericardial effusions and severe anaemia. The foetus will have gross

hepatosplenomegaly, cardiac and urogenital defects. Hb Bart’s hydrops foetalis

syndrome is uncommon in North America and North Europe, however it may be

more commonly encountered if these countries have more migrants coming from

Southeast Asia or South China. Another important form of alpha thalassaemia is

thalassaemia intermedia, Hb H disease is the typical example with 3 out of the 4

alpha genes being mutated or deleted [12]. Hb H disease is more prevalent in

countries with α0 thalassaemia, and the parents are α0 and α+ thalassaemia carriers.

Hb H disease has variable clinical severity from mild anaemia to transfusion

dependent thalassaemia. There is genotype-phenotype correlation among Hb H

disease [13]. Point mutations in critical regions of the α 1 or α 2 globin genes may

cause non-deletional α thalassaemia, and it is common in some regions such as

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Middle East. The non-deletional mutation of an alpha gene together with α0

thalassaemia results in more severe phenotype. There is geographical variation in

the types of point mutation [14,15]. In Southeast Asia and South China, Hb

Constant Spring (Hb CS, HBA2 c.427T > C) is one of the most common

non-deletional α-thalassaemia, there is a nucleotide substitution at the termination

codon of the α2-globin gene. Hb H Constant Spring results from the genotypes of

Hb CS plus α0 thalassaemia [16, 17].

1.2 Beta Thalassaemia

Beta globin gene is located at the chromosome 11 with one allele on each

chromosome. There are many different types of mutation of beta globin gene

identified, and over 300 mutations have been reported [18]. Some mutations lead

to complete absence of beta globin production, called β0, while some mutation

still have globin chain production but at markedly reduced rate, called β+

mutation. Beta thalassaemia carrier, or beta thalassaemia minor, is always

asymptomatic and only shows microcytosis and hypochromia of red cells in

blood test. Iron deficiency must be excluded in the setting of hypochromic

microcytic anaemia as this is correctable. The frequency of beta thalassaemia is

variable among different regions, from <1% to 16% [19]. Beta thalassaemia

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major is due to mutations of both beta globin genes leading to severe anaemia.

Without blood transfusion, the thalassaemia major patients may not survive

beyond three years of age. With regular blood transfusion and optimal iron

chelation therapy, many patients now survive into adulthood. There are reports of

properly managed thalassaemia major women having pregnancies and delivered

normal babies [20]. Allogeneic haematopoietic stem cell transplant from matched

sibling donors can provide curative treatment to thalassaemia major [21-23]. Beta

thalassaemia intermedia is another important form of thalassaemia. The patients

have both beta globin genes mutated but the mutation may be due to β+/β0, or

β+/β+. The degree of anaemia is not as severe as the beta thalassaemia major,

most patients have moderate severe anaemia and only requires occasional blood

transfusion [24]. Hb E mutation [beta26(B8)Glu-->Lys, GAG-->AAG] is

common in some parts of the world, with high incidence in Southeast Asia [25,

26]. The double heterozygotes of Hb E/β+ or β0 can produce the phenotype of

thalassaemia intermedia. With longer follow up of the thalassaemia intermedia

patients, they are found to have iron overload at older age and prone to develop

pulmonary hypertension and thrombosis [24]. These intermedia patients may

ultimately require regular blood transfusion and iron chelation therapy. The

heterogeneous clinical course of thalassaemia intermedia, Hb H disease and Hb

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E/β thalassaemia are attracting more attention from clinicians and they are

collectively called as Non-Transfusion-Dependent Thalassaemia (NTDT).

1.3 co-inheritance of different types of thalassaemia and haemoglobinopathies

Both alpha and beta thalassaemia are common in some countries, it would not be

rare for some individuals co-inherited both types of thalassaemia. The clinical

severity of thalassaemia is related to the absence of one type of globin chains,

either alpha or beta, and the relative excess of the other globin chain in the red

cells causing instability and haemolysis or ineffective erythropoiesis. The

co-inheritance of alpha and beta thalassaemia makes the imbalance of globin

chain production less severe, thus the red cells are less unstable. The end result is

less severe phenotype of the thalassaemia [27, 28]. The β0/β0 thalassaemia major

phenotype may be modified to the intermedia phenotype if co-inherited with α

thalassaemia. On the other hand, the co-inheritance of sickle cell trait with beta

thalassaemia trait will be associated with more severe sickle cell phenotype.

Incomplete genetic workup on affected individuals may under-estimate or

over-estimate the severity of the thalassaemia.

1.4 Migration and changing epidemiology

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In the past few centuries, we observed huge people mobility from one continent to

another continent. The typical example is the tremendous number of African

inhabitants being taken to North and South America after the New World was

discovered in 15th centuries. The sickle cell disease then becomes a common form

of haematological disease in America [29]. The colonization by European

countries also brought in large number of inhabitants from India Subcontinent and

Africa to Europe [30]. After the Vietnam War there were also large number of

Vietnamese refugees accepted by countries in Europe and North America [31]. In

the recent two decades with fast economic development in China and Southeast

Asian countries, more families now immigrate to European and American

countries for studying, business, family integration or seeking for better standard

of living. The most recent Syria crisis brings in over a million refugees from

Middle East across Turkey to central and western Europe. The migrants or

refugees are coming from areas with high incidence of thalassaemia and the

receiving countries are anticipated to see new generation of thalassaemia, from

thalassaemia trait to intermedia and major. Mediterranean countries in Europe

with high thalassaemia gene frequencies have already developed health systems

coping with thalassaemia, they may now face a new diversity of mutations which

are not commonly seen in their local population [33]. In a newborn screening

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study in California, Hb H disease is common among Southeast Asian immigrants,

including those of Laotian/Thai (26%), Filipino (15%), Chinese (15%),

Vietnamese (9%) and Cambodian (5%) ethnicity [33]. A recent study from the

Centers for Disease Control and Prevention at USA found that 27% of the US

thalassaemia patients were born outside US [24]. Among NTDT patients, 80% of

these patients were of minority population mainly coming from Southeast Asia,

Middle East and India. European countries will face great challenges from the

recent migrants from Middle East and North Africa. Only 5 countries have

established comprehensive programme to address the thalassaemia, namely Italy,

Greece, Cyprus, UK and France [32]. These countries have defined strategies to

tackle education, awareness programme and screening. The other European

countries need to get prepared for the emerging thalassaemia problem in their

countries. The changing epidemiology not only happens at international level, big

country like China with great variation in the incidence of thalassaemia among the

different provinces may face similar challenge with migration of population from

south to north. South China is having a high prevalence of alpha and beta

thalassaemia which is not seen in North China [34]. Health care workers need to

have knowledge on the epidemiology of thalassaemia of the countries where new

migrants originate from.

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2. Variation of genes in different ethnic groups

2.1 Alpha thalassaemia genotypes

α thalassaemia is the most common monogenic disorder, up to 20% of world

population carries the alpha thalassaemia genes [1]. Deletion or mutation of one (-α)

thalassaemia gene does not carry significant health problem. However countries

prevalent with both α-globin genes deletion (- -) from the same chromosome have

more severe forms of thalassaemia, either intermedia or major [35]. To set up

prenatal screening programme, the laboratories should know the genotypes of the

mutation to be tested. The more severe form of α thalassaemia involves deletion of

both α globin genes, and SEA deletion is the most common form. Single gene

deletion of α-globin gene is also common in Asia, deletion of 4.2 kb (leftward type,

-α4.2) and deletion of 3.7kb (rightward type, -α3.7). In Guangdong province of south

China, the prevalence of alpha thalassaemia is 12%, and the top three genotypes are

–SEA/αα (6.1%), α3.7α/αα (3.2%), and α4.2

α/αα (1.1%) [34]. With a high prevalence

of α0 and α+ thalassaemia carriers, Hb H disease is also relatively common (0.2%)

in the province. In Southeast Asia countries, α3.7 is much more common and

constitutes 95% of the single gene deletion [10]. However the -α4.2 deletion is more

frequent in Papua New Guinea and Vanuatu in Melanesia. Hb Constant Spring (Hb

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CS, HBA2 c.427T > C) and Hb Quong Sze (Hb QS, HBA2: c.377T > C) are the

two common non-deletional α-thalassaemia in Southeast Asia and South China, and

combined with α0 thalassaemia making the hemoglobin variant highly unstable

[35,36]. In Southeast Asia, there are other types of non-deletionalα-thalassaemia

reported, such as Hb Pakse, (TAA->TAT in α2 codon 142), Hb Suan-Dok

(CTG->CGG in α2 codon 109), Hb Pak Num Po (+T in α1 codon 131/132) and Hb

Adana (GGC->GAC in α2 codon 59) [26].

In the India Subcontinent, the prevalence of alpha thalassaemia varies from 10 to

25%, but some regions reported to have higher prevalence [10]. East India has a

high prevalence of alpha thalassemia of 50.8% with an allelic frequency of 0.37.

�3.7 is much more common than �

4.2 deletional thalassemia and were detected with

an allelic frequency of 0.33 and 0.04. In Santals of West Bengal the prevalence was

even up to 80% [37,38]. Alpha thalassaemia is also reported in South India but the

exact prevalence is not known, the diagnosis was made on Hb H inclusion bodies

[39]. Since α0 thalassaemia is not commonly found in India, the high prevalence of

alpha thalassaemia carrier rate does not cause significant health burden.

In Middle East, �3.7 deletional thalassemia is also the predominant type of alpha

thalassaemia; reported in Saudi Arabia (64%), Jordan (43%), United Arab Emirates

(28.4%), South Cyprus (72.8%), Oman (58.3%), Tunisia (22.5%) and Israel (51%)

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[9]. In an Iran study, �3.7 deletional mutation is 60.7% of alpha thalassaemia,

followed by � -5 nt deletion, 8.7%, and �4.2 deletional mutation only accounts for 2.8%

of alpha thalassaemia [40]. A report from Turkey also showed similar prevalence

for different deletion or non-deletional mutation, �3.7 in 43.81%; � -5 nt in 6.70%; -

-MED in 5.67% and α2Poly A2 in 2.57% [14]. In regions with higher prevalence of -

-MED, Hb H disease is also more commonly seen.

In the European countries, there is shift of the types of alpha thalassemia mutations.

In Greece, α–Med deletion was the most frequent deletion leading to α-thalassemia,

constituting 44.9% [41]. The more common �3.7 in Middle East and India

Subcontinent contributes 27.8% as the second common genotype. α-20.5 deletion

accounts for 15.9% of alpha thalassaemia mutation. Alpha thalassaemia is also

prevalent in Italy, and it was reported to have a high frequency of 38% in Sardinia

[42]. The most frequent mutation is �3.7 deletion, and 89% of the alpha

thalassaemia were identified to be carriers of one or two of the most common �3.7,

α–Med, α2 HphI, α2 NcoI, α1 NcoI thalassemic alleles. The higher prevalence of α–Med

deletion will lead to higher chance of Hb Bart’s hydrops foetalis syndrome and

additional effort should be spent in prenatal diagnosis for prevention [43]. Hb H

disease is also more common with such genetic background. Spain also has high

prevalence of alpha thalassaemia and the allelic frequency is 1.4-2.4%, and the

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mutation is mostly �3.7 deletion [44]. Other types of mutation are also observed,

�4.2 deletion is occasionally detected and α–Med and α–SEA deletion had also been

reported.

In African countries, alpha thalassaemia gene mutation is also common. �3.7

deletional thalassemia is having gene frequency of 0.21 in Nigeria. Northern Africa

share similar genotype frequency as other Mediterranean countries [45]. A

Summary of the common alpha mutations is shown in Table 1.

2.2 Beta Thalassaemia genotpes

The beta-globin gene has two intervening sequences (IVS) and three exons. The

mutation of these various regions differs in frequency geographically. Globally IVS-I

is most susceptible to mutations followed by exon 1 and exon 2, and IVS-II less

frequent and exon 3 being the least common [18]. The frequency of beta thalassaemia

mutations ranges from <1.0 to 16.0%, being 3.5-3.8% in South China, 3.0–4.0% in

India, 4–11.0% in Middle East countries, 1.5–3.0% in North Africa. The

Mediterranean countries also have high prevalence of beta thalassaemia, Cyprus was

reported to have 17.2%, but with a drop of prevalence in recent two decade down to

12.1% after implementation of prenatal screening [46].

In South China, the common mutations are codons 41/42, codon 17 (A>T), - 28 (A>G)

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and IVS-II-654 (C>T) which account for 86.0% of the cases studied [34]. In

Southeast Asia, β0 thalassaemia is more common than β+ thalassaemia. Thailand has

the beta thalassaemia carrier rate of 3–9% but it is 10–50% for HbE [26]. The three

most common mutant alleles of beta thalassaemia in Thailand are similar to those of

China, being codons 41/42, codon 17 and the substitution at nucleotide -28. The

others were codons 71/72, IVS-I-1, IVS-II-654. In South Vietnam, beta thalassaemia

carrier rate is 1.5-25%, codons 41/42 is most common (35.3%) followed by codon 17

(A>T) (25.0%) and -28 (A>G) 7.3%, codons 71/72 (+A) (7.3%), IVS-II nt 654 (C>T)

(7.3%), and IVS-I nt 1 (G>T) (6.0%) [25]. In Indonesia, the most frequent beta globin

gene mutation is HbE (28.2%), followed by IVS1-nt5 (43.5%), and Cd 35 (8%) [47].

In India, the prevalence of beta thalassaemia varies with the regions and communities,

it is higher for Punjabis, Sindhis, Gujaratis, Bengalis, central and eastern and western

parts of the country, but lower in south part [48]. Among the mutations, IVS-I-5, 619

bp deletion, IVS-I-1 (G>T), codons 41/42 and codons 8/9 comprise 82.5% of all beta

thalassaemia alleles in India, and IVS-I-5 being the most common allele. The

prevalence of IVS-I-5 allele varies from 44.8% in the north to 67.0% in the south,

71.4% in the east. In Pakistan, the common mutations include IVS-I-5, codons 8/9,

the 619 bp deletion and IVS-I-1 (G>T), codons 41/42, and their frequency also varies

from region to region.

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In the Arab countries, the beta thalassaemia carrier rate is 2-10%. In Syria, 10 most

frequent mutations constituted 77.5% of beta thalassaemia mutations [49]. These

mutations included IVS-I-110 (G > A) (17.0%), IVS-I-1 (G > A) (14.7%), codon

39 (C > T) (14.4%), IVS-II-1 (G > A) (9.8%), codon 8 (-AA) (6.2%), IVS-I-6 (T >

 C) (5.2%), IVS-I-5 (G > C) (4.9%), codon 5 (-C) (3.2%), IVS-I-5 (G > A) (3.2%)

and codon 37 (G > A) (2.2%), another 21 mutations were less frequent or sporadic.

The prevalence of β-thalassemia carrier varies between 3.7 and 4.6% in different parts

of Iraq [50,51]. In the Arab population of Iraq, 6 mutations constituted about 78.0% of

the cases, and included 3 Mediterranean mutations namely: IVS-I-110 (30.1%),

IVS-II-1 (18.4%) and IVS-I-1 (7.8%). There were also Asian Indian mutations

identified, namely: IVS-I-5 (9.7%) and codons 8/9 (6.8%), and Kurdish codon 44

mutation was also noted (4.9%). In Northwestern Iraq, the most frequent mutation

was IVS-I-110 (G>A) documented in 34 %, followed by IVS-I-6 (T>C) in 9.6 %,

IVS-I-5(G>C) in 8.5 %, codon 39 (C>T) and codon 44 (-C) in 7.4 % each. In Kurds,

eight mutations represented 96% of the mutated beta globin genes. These were

IVS-II-1 (G>A), IVS-I-110 (G>A), codon 8 (-AA), codons 8/9 (+G), IVS-I-5 (G>C),

codon 5 (-CT), IVS-I-6 (T>C) and IVS-I-1 (G>A).

Iran is also having high prevalence of beta thalassaemia carrier rate. Studies have

revealed more than 47 different beta globin gene mutations in Iran [48]. The

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predominant mutation IVS-II-1 (G >A) is followed by the IVS-I-5 (G > C), the

codons 8/9, the IVS-I-110 (G > A) and IVS-I-1(G > A). These mutations are

responsible for more than 85% of the beta thalassemia mutations in Iran. In south

Turkey, the common beta thalassemia gene mutations included: IVS-I.110 (G > A) in

35.1%, codon 8 (-AA) in 9.1%, IVSI.1 (G > A) in 8.6%, IVSI.6 (T > C) in 7.6% and

-30 (T > A) in 7.4% [52]. In west Turkey, 7 mutations accounted for 85.3% of the

mutated alleles, namely IVS-I-110 (G > A) (41.7%), IVS-I-1 (G > A) (8.9%),

IVS-II-745 (C > G) (8.6%), codon 8 (-AA) (7.7%), IVS-II-1 (G > A) (7.2%),

IVS-I-6 (T > C) (6.6%), codon 39 (C > T) (4.6%) [53].

In Europe, Codon 39 mutation is the most frequent mutation. In Sicily, the codon 39

mutation accounts for 31.8% of β-thalassemia followed by IVS I-110 (26.66%), IVS

I-6 (14.62%), IVS I-1 (9.19%), IVS II-745 (5.87%), −87 G>C (2.57%), IVS II-1

(2.28%) and Sicilian δβ-deletion (2.07%) [54]. These eight mutations accounted for

95.11% of β- thalassemia alleles. In Spain, Codon 39 mutation is present in 64.0% of

cases followed by the IVS-I-1 and IVS-I-110 mutations [54]. In Greece, codon 39,

IVS-I-1, IVS-I-6, IVS-I-110, IVS-II-1 and IVS-II-745 account for 91.4% of the

thalassemia alleles [41]. Summary of common beta thalassaemia mutations is shown

in Table 2.

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3. Prenatal diagnosis and genetic counselling

Prenatal diagnosis and therapeutic abortion is the most effective way to prevent severe

thalassaemia. In some countries, premarital screening and genetic counselling

(PMSGC) has been implemented [55]. Cyprus, Greece and Italy have demonstrated

successful prevention of new cases of thalassaemia major. However studies showed

that the effect of mandatory PMSGC is less satisfactory in Middle East countries [56].

PMSGC programme aims to reduce beta thalassaemia births through prevention of

at-risk marriages by discouragement during counselling and, where legally feasible,

termination of affected foetuses through prenatal diagnosis and therapeutic abortion.

Findings suggest that programmes in Saudi Arabia and Jordan only achieved 10 and

40% reductions in at-risk marriage rates respectively. Due to religious or cultural

reasons, some countries do not allow legal therapeutic abortion. Given the low

marriage cancellation rates and that abortion is not accepted in some ethnic groups, it

is difficult to achieve effective control of thalassaemia births. Consanguinity is

particularly common in some population, can be up to 20-40%, and the high

thalassaemia carrier rates in these population will introduce a high chance of severe

thalassaemia [30]. With influx of migrants from these high prevalent countries, the

receiving countries must prepare for the emerging thalassaemia population. Some

migrants may be socio-economically under-privileged or not cover by medical

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insurance. Free prenatal service should be offered to these migrants so a timely

prenatal test may be performed at the right timing. The cost of prenatal screening and

testing is far below the cost of providing life-long medical treatment for thalassaemia

major patient, this is the most cost-effectisve management for this problem [3].

Planning for a prenatal diagnostic programme, the prenatal diagnostic centres should

have knowledge of the genetic background of the pregnant women. Some countries

such as North European countries have very low incidence of thalassaemia, there may

not be established screening programme for thalassaemia. Countries like France and

UK have long history of accepting immigrants from high prevalent areas of

thalassaemia such as India and North Africa, they have established screening

programmes in place. However the challenges of these countries are the new

thalassaemia mutations and sociocultural differences. The prenatal laboratories will

encounter some new mutations they seldom detected previously. The timely

identification and diagnosis is crucial for prenatal diagnosis and therapeutic

intervention. The great heterogeneity of alpha and beta thalassaemia mutation in

different ethnic groups would be challenging [10,18].

Genetic counselling of new migrants may also encounter difficulties. Language

barrier may affect the accuracy of history taking. Social and cultural factors may

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cause delay of first antenatal visit and may even miss the optimal timing of

performing prenatal test or therapeutic abortion. In some ethnic groups, the families

may not understand or accept therapeutic abortion. There is variation in practice of

legal abortion even among Muslim countries, some allow unrestricted access to

abortion while some permit abortion in the first 4 months for foetal deformities, but

some countries is illegal to have abortion even for foetal impairment [55]. Migrants

coming from these countries may have different interpretation on therapeutic abortion,

genetic counsellors should have knowledge on the background. Another important

component of genetic counselling is the prediction of the disease severity after birth

of the babies. For well-described conditions such as Hb Bart’s hydrops foetalis

syndrome, the counselling is usually strict forward. However new medical

intervention may also alter the clinical course of a universally fatal condition, such as

intra-uterine transfusion followed by successful post-natal stem cell transplant for Hb

Bart’s disease [57-60]. Hb H-Constant Spring typically has moderate anaemia and

does not require life-long transfusion. There was report that hydrops foetalis occurred

in a foetus with Hb H-Constant Spring, and it was recommended that fetus with Hb

H-Constant Spring disease should be followed by serial ultrasound after a gestational

age of 20 weeks and if fetal hydrops is identified, intrauterine transfusion should be

considered [61]. Successful outcomes have been reported following intrauterine

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transfusion for Hb H hydrops foetalis disease [62].

Beta thalassaemia major requires life-long transfusion and intensive iron chelation

therapy. Traditionally the daily subcutaneous infusion of desferrioxamine was

associated with poor quality of life, suboptimal compliance of chelation therapy and

also high incidence of iron overload complications and shortened survival [63]. With

the introduction of effective oral iron chelators, deferiprone and deferasirox, the

efficacy of iron chelation is much improved and also with reduction of iron overload

complications [64, 65]. There are now more thalassaemia major patients survive into

adulthood. An Italian multicenter study demonstrated that thalassaemia major patients

born after 1970, there was 92.2% survival at age of 25 for females, and 65% survived

at age of 35 years [66, 67]. A UK study also showed similar improvement of survival

of thalassaemia major patients after introduction of iron chelators [68]. With the

introduction of oral chelators and better monitoring of body iron by MRI imaging of

heart and liver in recent years, the improved drug compliance and drug efficiency will

further enhance the survival. It is anticipated that more thalassaemia major women

can now be pregnant but they may have more complications during pregnancy, such

as increasing anaemia, increasing iron overload due to avoidance of iron chelators

during early pregnancy, preeclampsia and congestive heart failure [20, 69-70]. They

need special care from joint care of haematologists and obstetricians. Similarly some

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thalassaemia intermedia patients may also develop similar complications during

pregnancy and require more close monitoring [24]. More couples of thalassaemia

carriers are now accepting continuation of pregnancy even prenatal diagnosis

confirming foetus being diagnosed thalassaemia major. Counselling of foetus with

genetic mutation of thalassaemia intermedia or

non-transfusion-dependent-thalassaemia (NTDT) can be difficult as the clinical

course may be unpredictable [71]. Some thalassaemia intermedia patients may have

relatively normal quality of life in childhood and adolescent periods, they may

develop cardiac and pulmonary complications later in life, and some may have

complications of thromboembolism [24]. The genotype-phenotype correlation may

not be accurately predicted, and there may also be interactions from other mutations,

such as co-inheritance of alpha and beta thalassaemia.

Summary

Mobility of world population, either from immigration or refugees, is getting more

and more common. Countries traditionally not having thalassaemia mutation in the

native people are now facing the challenge of influx of people carrying the

thalassaemia mutation into their community. North America and Australia are popular

countries among Southeast Asian and Chinese immigrants. The Syria and Iraq

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refugees move into North European countries may stay in these countries and deliver

the next generation. To avoid the great long-term health burden from managing the

thalassaemia major, these countries must plan for effective screening and prenatal

diagnosis system to cater for the new migrants. The genetic subtypes of migrants vary

according to the ethnic groups. Some mutations are more prevalent in some ethnic

groups while some mutations are only found in particular ethnic groups. The clinical

course of thalassaemia major is now modified by the effective oral iron chelation.

Thalassaemia intermedia or NTDT have heterogeneous clinical presentation and

sometimes the phenotype is modified by co-inheritance of another thalassaemia

mutation. Social and cultural differences may be a barrier for timely prenatal test.

Free prenatal screening is essential to make the system working as some of the

migrants may not have insurance cover. The cost of prenatal diagnosis is found to be

much lower than the life-long treatment. The health care workers should be equipped

with knowledge on this ‘new’ disease. Effective screening and prevention requires

support from government policy, public awareness and appropriate prenatal diagnosis

programme.

Practice points

� Migrants from thalassaemia prevalent regions may carry different types of

thalassaemia mutations according to ethnic background

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� Prenatal screening and diagnosis programme should cover for the types of

mutation in the relevant ethnic groups

� Consanguinity is common in some ethnic groups and they are particularly

prone to have severe types of thalassaemia in the newborns

� The survival outcome of severe or intermedia thalassaemia is affected by

the treatment provided, especially the iron chelation therapy and stem cell

transplantation

� Genetic counseling should include the option of continuation of pregnancy

that may lead to severe phenotype requiring life long treatment and

suboptimal quality of life.

Research agenda

� Epidemiology of thalassaemia diseases with the influx of migrants

� Effectiveness of thalassaemia prevention programme

� Strategies in management of complications in pregnant women and affected

foetuses with thalassaemia major and intermedia

"Conflict of interest statement" : There is not any financial and personal relationships

with other people or organisations that could inappropriately influence (bias) the

content of this article.

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ACCEPTED MANUSCRIPTTable 1: Common Alpha-thalassaemia mutations

Regions Types Mutation Remarks

South-East Asia α0

- - SEA

Most common deletion among Asians and world

wide

- - FIL

Mainly in Philippinians

- - THAI

Common among Thai

α+ - α

3,7 Relatively common

- α4,2

Less common

α Constant Spring

One of the most common non-deletion variants in

Chinese

α Suan Dok

Highly unstable α-chain

α Quong Sze

Highly unstable α-chain

α Paksé

Highly unstable α-chain, found in Thai, Laotian

α init A-G

Common in Vietnam

India α+ - α

3,7 Common

- α4,2

Less common

α Koya Dora

Relatively rare

α IVS I-117

Relatively rare

α+

- α

0 α

PA3 (AATA - -) Found in Hindustani from Surinam

Middle East α0 - -

MED I Common in Iran, Arab population

α+

- α3,7

Common in Iran, Arab population

α+

- α

0 α

PA1 (AATAAG) Relatively common in Arab population

African, Afro-American

and Afro-Caribbean

α0 - α

3,7 init GTG One of the few α

0-thal alleles in African population

- α3,7 init (-2 bp)

One of the few α0-thal alleles in North-African

population

α+ - α

3,7 Common

- α3,7 Cd14 T>G

Hb Evanston, relatively rare,

α Seal Rock

Relatively rare

Mediterranean α0 - -

MED I Relatively frequent in Greece, Cyprus, Turkey

- - MED II

Relatively rare, Southern Italy, Greece, Turkey

- (α)20.5

Common in Greece, Cyprus, Turkey

α+ - α

3.7 Common in Mediterranean populations

α IVS I (-5 nt)

Relatively common

αα cd119C>T

Hb Groene Hart, common in Moroccan, Tunisian

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ACCEPTED MANUSCRIPTTable 2 – Common ß-thalassaemia mutations

Regions Types Mutation Remarks

South-East Asia ß0

CD41/42–TTCT Chinese, SE Asians

CD17, A→T

Chinese, SE Asians

CD43, G →T

Chinese, Thai

IVS2–654, C→T

Chinese, SE Asians

CD71/72, +A

Chinese, Thai

CD27/28, +C Chinese, Thai

CD14/15, +G Chinese

IVS1-5, G→C SE Asians

ß+ –28, A→G Chinese, SE Asians

CAP +40 to +43 Chinese

–29, A→G Chinese

IVS1-I, G→T SE Asian, Chinese

–32, C→A Taiwanese

–30, T→C Chinese

Indian Subcontinent ß0 IVS1-5, G→C

India, Pakistan, Bangladesh, Sri Lanka, Mauritius

IVS1-I, G→A

Sri Lanka

IVS1-I, G→T India

CD47/48, +ATCT India

619 bp deletion India, Pakistan

Codon 41/42, –TCCT India

ß+

Codon 8/9, +G India, Bangladesh

Codon 15, G→A India

Codon 8/9, +G India, Pakistan

–88, C→T India

Middle East ß0 Codon 36/37 –T Iran

IVS1-I Iran, Iraq, Kurd, Syria

IVS1-5

Iraq, Iran

IVS2-I

Iran, Arab, Syria

CD5, –CT Syria

ß+ IVS2-745 Iran

IVS1-6 Syria, Iraq, Kurd, Arab

IVS1-110 Syria, Iraq, Kurd, Arab

Codon 8/9, +G Iraq, Iran, Arab

African origin ß0 CD39, C→T Tusnia, Algeria, Morocco

IVS1-I Tusnia, Algeria, Morocco

Codon 8, -AA Morocco

ß+ IVS1-6 Tusnia, Algeria, Morocco

–29, A→G Algeria, Morocco

Mediterranean ß0 Codon 39

Mediterranean

IVS1-I

Mediterranean

–IVS-2-1 Mediterranean

ß+ IVS-1-110 Mediterranean

IVS-2-745

Mediterranean

IVS-1-6 Mediterranean

IVS-1-5 Mediterranean

IVS-2-745 Mediterranean

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Highlights:

� Thalassaemia mutation is common in some ethnic groups

� Prenatal screening and diagnosis can prevent severe cases

� Countries receiving migrants to establish prenatal thalassaemia

screening programme