Thalassaemia is the most common monogenic disorder worldwide. It is common in areas with prevalent malaria as thalassaemic red cells provide immunity against the parasite. The incidence of thalassaemia carriers is high in regions such as Mediterranean, Middle East, Indian subcontinent, Southeast Asia and 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 non-prevalent countries may not have established pre-natal screening system for thalassaemia. The genetic subtypes among the different ethnic groups vary; this may pose challenges in prenatal diagnosis. Genetic counselling on the postnatal course of thalassaemia may be affected by the genotype–phenotype correlation and coinheritance of other genetic diseases. New treatment methods improve the survival of patient with thalassaemia major, but some late complications that occur with longer survival have been recently discovered.
Highlights
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Thalassaemia mutation is common in some ethnic groups.
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Prenatal screening and diagnosis can prevent severe cases.
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Countries receiving migrants should establish prenatal thalassaemia screening programme.
Background
Thalassaemia is the most common monogenic disorder worldwide. Approximately 20% of the world population carries α + thalassaemia and 5.2% of the population carries a significant variant of the haemoglobin disorder including β–thalassaemia and α 0 -thalassaemia . Carriers of thalassaemia genes are protected from falciparum malaria, and it is common in countries from the Mediterranean region to the east, including Middle East, Indian subcontinent, Southeast Asia and South China . Each year approximately 56,000 babies are born with major thalassaemia. Majority of the major thalassaemia patients require regular blood transfusion and also iron chelation therapy . Although the survival of thalassaemia major patients is improving and most of them survive beyond adulthood, the quality of life and ultimate life expectancy are still suboptimal . There is a considerable financial burden on the family and the community for the expensive life-long treatment. Prevention programmes for thalassaemia major in endemic areas have been shown to be successful in regions such as in Cyprus and Sardinia . A successful prevention programme requires efforts such as government policy, public education, genetic counselling, prenatal screening and diagnosis . In the recent few decades, mobility and migration of people to other countries has been rapidly increasing, and thalassaemia non-prevalent countries are now facing the problem of increasing number of babies born with thalassaemia major . Health care workers in the non-prevalent countries should prepare for the prevention and management of the ‘new’ disease.
Genetics of thalassaemia
α-thalassaemia
Thalassaemia is caused by mutation or deletion of the α- or β-globin genes, which leads to the reduction or total absence of globin chain production. The α-thalassaemia gene is located on chromosome 16 with two α-globin genes, α 1 and α 2. Approximately 90% of the mutations are deletional type: deletion of one (-α) or both (- -) α-globin genes from the chromosome . If only one of the four alleles is mutated or deleted (α + carrier) the individual is asymptomatic and the red cell indices are usually normal. α + -Thalassaemia is 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 α genes on the same chromosome are mutated or deleted, there will be total absence of α-globin production from that chromosome, and this is recognised as α 0 -thalassaemia. The carrier of α 0 -thalassaemia (thalassaemia trait) has microcytosis of red cells and may have mild anaemia; however, most of them are asymptomatic and are detected only on routine blood test investigations. α 0 -Thalassaemia is common in some parts of the world, such as – SEA , deletion of the two α genes that is prevalent in Southeast Asia and South China . The double gene deletion – – MED is prevalent in Mediterranean regions such as Cyprus, whereas – – FIL is prevalent in the Philippines. In α 0 -thalassaemia, the offspring has a 25% chance of having Hb Bart’s hydrops foetalis syndrome or α-thalassaemia major if both couples are α 0 -thalassaemia carriers . Hb Bart’s syndrome is characterised by foetal onset of generalised oedema, pleural and pericardial effusions and severe anaemia. The foetus will have gross hepatosplenomegaly and cardiac and urogenital defects. Hb Bart’s hydrops foetalis syndrome is uncommon in North America and Northern Europe; however, it may be more common if these countries have more migrants coming from Southeast Asia or South China. Another important form of α-thalassaemia is thalassaemia intermedia; Hb H disease is the typical example with three out of the four α genes being mutated or deleted . Hb H disease is more prevalent in countries with α 0 thalassaemia, and the parents are α 0 and α + thalassaemia carriers. Hb H disease has variable clinical severity that can range from mild anaemia to transfusion-dependent thalassaemia. There is genotype–phenotype correlation among Hb H disease . 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 Middle East. The non-deletional mutation of an α gene together with α 0 -thalassaemia results in more severe phenotype. There is a geographical variation in the types of point mutation . 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 α 0 -thalassaemia .
β-Thalassaemia
β-Globin gene is located on the chromosome 11 with one allele on each chromosome. There are many different types of mutations of β-globin gene identified, and more than 300 mutations have been reported . Some mutations lead to complete absence of β-globin production, called β 0 , whereas some mutations still have globin chain production but at markedly reduced rate, called β + mutation. β-Thalassaemia carrier patients (β-thalassaemia minor) are always asymptomatic and only show 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 β-thalassaemia is variable among different regions, from <1% to 16% . β-Thalassaemia major is due to mutations of both β-globin genes leading to severe anaemia. Without blood transfusion, patients with thalassaemia major may not survive beyond 3 years of age. With regular blood transfusion and optimal iron chelation therapy, many patients now survive into adulthood. There are reports of women with thalassaemia major who received proper management of the disease having pregnancies and delivered normal babies . Allogeneic haematopoietic stem cell transplant from matched sibling donors can provide curative treatment to thalassaemia major . β-Thalassaemia intermedia is another important form of thalassaemia. The patients have both β-globin genes mutated, but the mutation may be due to β + /β 0 or β + /β + . The degree of anaemia is not as severe as the β-thalassaemia major; most patients have moderate severe anaemia and only require occasional blood transfusion . Hb E mutation [β26(B8)Glu–>Lys, GAG–>AAG] is common in some parts of the world, with high incidence in Southeast Asia . The double heterozygotes of Hb E/β + or β 0 can produce the phenotype of thalassaemia intermedia. With longer follow-up of patients with thalassaemia intermedia, they are found to have iron overload at older age and prone to develop pulmonary hypertension and thrombosis . These patients may ultimately require regular blood transfusion and iron chelation therapy. The heterogeneous clinical course of thalassaemia intermedia, Hb H disease and Hb E/β-thalassaemia is attracting more attention from clinicians, and these are collectively called as non-transfusion-dependent thalassaemia (NTDT).
Coinheritance of different types of thalassaemia and haemoglobinopathies
As both α- and β-thalassaemia are common in some countries, it would not be rare for some individuals to coinherit both types of thalassaemia. The clinical severity of thalassaemia is related to the absence of one type of globin chains, either α or β, and the relative excess of the other globin chain in the red cells causing instability and haemolysis or ineffective erythropoiesis. The coinheritance of α- and β-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 . The β 0 /β 0 thalassaemia major phenotype may be modified to the intermedia phenotype if coinherited with α-thalassaemia. On the other hand, the coinheritance of sickle cell trait with β-thalassaemia trait will be associated with more severe sickle cell phenotype. Incomplete genetic work-up on affected individuals may underestimate or overestimate the severity of the thalassaemia.
Migration and changing epidemiology
In the past few centuries, we observed huge mobility of people from one continent to another continent. A typical example is the tremendous number of African inhabitants taken to North and South America after the New World was discovered in the 15th century. The sickle cell disease then became a common form of haematological disease in America . The colonisation by European countries also brought in large number of inhabitants from Indian subcontinent and Africa to Europe . After the Vietnam War, there were also large number of Vietnamese refugees accepted by countries in Europe and North America . 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 better standard of living. The most recent Syrian crisis brought in over a million refugees from Middle East across Turkey to central and western Europe. The migrants or refugees come 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. Although Mediterranean countries in Europe with high thalassaemia gene frequencies have already developed health systems to cope with thalassaemia, they may now face a new diversity of mutations that are not commonly seen in their local population . In a new-born screening study in California, Hb H disease was common among Southeast Asian immigrants, including those of Laotian/Thai (26%), Filipino (15%), Chinese (15%), Vietnamese (9%) and Cambodian (5%) ethnicity . A recent study from the Centers for Disease Control and Prevention at USA found that 27% of the US thalassaemia patients were born outside the USA . Among patients with NTDT, 80% of these patients belonged to 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 five countries have established comprehensive programmes to address the thalassaemia, namely Italy, Greece, Cyprus, UK and France . These countries have defined strategies to tackle education, awareness programme and screening. The other European countries need to prepare for the emerging thalassaemia problem in their countries. The changing epidemiology takes place not just at the international level. Big countries such as China with great variation in the incidence of thalassaemia among the different provinces may face similar challenges with migration of population from south to north. South China has a high prevalence of α- and β-thalassaemia that is not seen in North China . Health care workers need to be equipped with knowledge on the epidemiology of thalassaemia of the countries where the new migrants originate from.
Genetics of thalassaemia
α-thalassaemia
Thalassaemia is caused by mutation or deletion of the α- or β-globin genes, which leads to the reduction or total absence of globin chain production. The α-thalassaemia gene is located on chromosome 16 with two α-globin genes, α 1 and α 2. Approximately 90% of the mutations are deletional type: deletion of one (-α) or both (- -) α-globin genes from the chromosome . If only one of the four alleles is mutated or deleted (α + carrier) the individual is asymptomatic and the red cell indices are usually normal. α + -Thalassaemia is 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 α genes on the same chromosome are mutated or deleted, there will be total absence of α-globin production from that chromosome, and this is recognised as α 0 -thalassaemia. The carrier of α 0 -thalassaemia (thalassaemia trait) has microcytosis of red cells and may have mild anaemia; however, most of them are asymptomatic and are detected only on routine blood test investigations. α 0 -Thalassaemia is common in some parts of the world, such as – SEA , deletion of the two α genes that is prevalent in Southeast Asia and South China . The double gene deletion – – MED is prevalent in Mediterranean regions such as Cyprus, whereas – – FIL is prevalent in the Philippines. In α 0 -thalassaemia, the offspring has a 25% chance of having Hb Bart’s hydrops foetalis syndrome or α-thalassaemia major if both couples are α 0 -thalassaemia carriers . Hb Bart’s syndrome is characterised by foetal onset of generalised oedema, pleural and pericardial effusions and severe anaemia. The foetus will have gross hepatosplenomegaly and cardiac and urogenital defects. Hb Bart’s hydrops foetalis syndrome is uncommon in North America and Northern Europe; however, it may be more common if these countries have more migrants coming from Southeast Asia or South China. Another important form of α-thalassaemia is thalassaemia intermedia; Hb H disease is the typical example with three out of the four α genes being mutated or deleted . Hb H disease is more prevalent in countries with α 0 thalassaemia, and the parents are α 0 and α + thalassaemia carriers. Hb H disease has variable clinical severity that can range from mild anaemia to transfusion-dependent thalassaemia. There is genotype–phenotype correlation among Hb H disease . 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 Middle East. The non-deletional mutation of an α gene together with α 0 -thalassaemia results in more severe phenotype. There is a geographical variation in the types of point mutation . 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 α 0 -thalassaemia .
β-Thalassaemia
β-Globin gene is located on the chromosome 11 with one allele on each chromosome. There are many different types of mutations of β-globin gene identified, and more than 300 mutations have been reported . Some mutations lead to complete absence of β-globin production, called β 0 , whereas some mutations still have globin chain production but at markedly reduced rate, called β + mutation. β-Thalassaemia carrier patients (β-thalassaemia minor) are always asymptomatic and only show 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 β-thalassaemia is variable among different regions, from <1% to 16% . β-Thalassaemia major is due to mutations of both β-globin genes leading to severe anaemia. Without blood transfusion, patients with thalassaemia major may not survive beyond 3 years of age. With regular blood transfusion and optimal iron chelation therapy, many patients now survive into adulthood. There are reports of women with thalassaemia major who received proper management of the disease having pregnancies and delivered normal babies . Allogeneic haematopoietic stem cell transplant from matched sibling donors can provide curative treatment to thalassaemia major . β-Thalassaemia intermedia is another important form of thalassaemia. The patients have both β-globin genes mutated, but the mutation may be due to β + /β 0 or β + /β + . The degree of anaemia is not as severe as the β-thalassaemia major; most patients have moderate severe anaemia and only require occasional blood transfusion . Hb E mutation [β26(B8)Glu–>Lys, GAG–>AAG] is common in some parts of the world, with high incidence in Southeast Asia . The double heterozygotes of Hb E/β + or β 0 can produce the phenotype of thalassaemia intermedia. With longer follow-up of patients with thalassaemia intermedia, they are found to have iron overload at older age and prone to develop pulmonary hypertension and thrombosis . These patients may ultimately require regular blood transfusion and iron chelation therapy. The heterogeneous clinical course of thalassaemia intermedia, Hb H disease and Hb E/β-thalassaemia is attracting more attention from clinicians, and these are collectively called as non-transfusion-dependent thalassaemia (NTDT).
Coinheritance of different types of thalassaemia and haemoglobinopathies
As both α- and β-thalassaemia are common in some countries, it would not be rare for some individuals to coinherit both types of thalassaemia. The clinical severity of thalassaemia is related to the absence of one type of globin chains, either α or β, and the relative excess of the other globin chain in the red cells causing instability and haemolysis or ineffective erythropoiesis. The coinheritance of α- and β-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 . The β 0 /β 0 thalassaemia major phenotype may be modified to the intermedia phenotype if coinherited with α-thalassaemia. On the other hand, the coinheritance of sickle cell trait with β-thalassaemia trait will be associated with more severe sickle cell phenotype. Incomplete genetic work-up on affected individuals may underestimate or overestimate the severity of the thalassaemia.
Migration and changing epidemiology
In the past few centuries, we observed huge mobility of people from one continent to another continent. A typical example is the tremendous number of African inhabitants taken to North and South America after the New World was discovered in the 15th century. The sickle cell disease then became a common form of haematological disease in America . The colonisation by European countries also brought in large number of inhabitants from Indian subcontinent and Africa to Europe . After the Vietnam War, there were also large number of Vietnamese refugees accepted by countries in Europe and North America . 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 better standard of living. The most recent Syrian crisis brought in over a million refugees from Middle East across Turkey to central and western Europe. The migrants or refugees come 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. Although Mediterranean countries in Europe with high thalassaemia gene frequencies have already developed health systems to cope with thalassaemia, they may now face a new diversity of mutations that are not commonly seen in their local population . In a new-born screening study in California, Hb H disease was common among Southeast Asian immigrants, including those of Laotian/Thai (26%), Filipino (15%), Chinese (15%), Vietnamese (9%) and Cambodian (5%) ethnicity . A recent study from the Centers for Disease Control and Prevention at USA found that 27% of the US thalassaemia patients were born outside the USA . Among patients with NTDT, 80% of these patients belonged to 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 five countries have established comprehensive programmes to address the thalassaemia, namely Italy, Greece, Cyprus, UK and France . These countries have defined strategies to tackle education, awareness programme and screening. The other European countries need to prepare for the emerging thalassaemia problem in their countries. The changing epidemiology takes place not just at the international level. Big countries such as China with great variation in the incidence of thalassaemia among the different provinces may face similar challenges with migration of population from south to north. South China has a high prevalence of α- and β-thalassaemia that is not seen in North China . Health care workers need to be equipped with knowledge on the epidemiology of thalassaemia of the countries where the new migrants originate from.
Variation of genes in different ethnic groups
α-Thalassaemia genotypes
α-Thalassaemia is the most common monogenic disorder, and up to 20% of world population carries the α-thalassaemia genes . Deletion or mutation of one (-α) thalassaemia gene does not result in notable 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 . To set up prenatal screening programmes, the laboratories should know the genotypes of the mutations 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, -α 4.2 ) and deletion of 3.7 kb (rightward type, -α 3.7 ). In Guangdong province of South China, the prevalence of α-thalassaemia is 12%, and the top three genotypes are – SEA /αα (6.1%), α 3.7 α/αα (3.2%) and α 4.2 α/αα (1.1%) . With a high prevalence of α 0 – and α + -thalassaemia carriers, Hb H disease is also relatively common (0.2%) in this region. In the countries of Southeast Asia, α 3.7 is much more common and constitutes 95% of the single gene deletion . However, the -α 4.2 deletion is more frequent in Papua New Guinea and Vanuatu in Melanesia. Hb CS (HBA2 c.427T > C) and Hb Quong Sze (Hb QS, HBA2: c.377T > C) are the two common non-deletional forms of α-thalassaemia in Southeast Asia and South China, and combining with α 0 -thalassaemia makes the haemoglobin variant highly unstable . In Southeast Asia, there are other types of non-deletional α-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) .
In the Indian subcontinent, the prevalence of α-thalassaemia varies from 10% to 25%, but some regions reported to have higher prevalence . East India has a high prevalence of α-thalassemia of 50.8% with an allelic frequency of 0.37. α 3.7 is much more common than α 4.2 deletional thalassemia and was detected with an allelic frequency of 0.33 and 0.04. In the Santals of West Bengal, the prevalence was even up to 80% . α-Thalassaemia is also reported in South India, but the exact prevalence is not known; the diagnosis was made on Hb H inclusion bodies . Because α 0 -thalassaemia is not commonly found in India, the high prevalence of α-thalassaemia carrier rates does not cause significant health burden.
In the Middle East, α 3.7 deletional thalassemia is also the predominant type of α-thalassaemia: Saudi Arabia (64%), Jordan (43%), the United Arab Emirates (28.4%), South Cyprus (72.8%), Oman (58.3%), Tunisia (22.5%) and Israel (51%) . In an study from Iran, α 3.7 deletional mutation was found in 60.7% of α-thalassaemia, followed by α −5 nt deletion (8.7%) and α 4.2 (2.8%) . A report from Turkey also showed similar prevalence for different deletion or non-deletional mutations: α 3.7 in 43.81%, α −5 nt in 6.70%, – – MED in 5.67% and α2 Poly A2 in 2.57% . In regions with higher prevalence of – – MED , Hb H disease is also more common.
In the European countries, there is shift in the types of α-thalassemia mutations. In Greece, α –Med deletion was the most frequent deletion leading to α-thalassemia, constituting 44.9% . The more common α 3.7 in the Middle East and Indian subcontinent accounts to 27.8% and is the second most common genotype. α -20.5 deletion accounts for 15.9% of α-thalassaemia mutations. α-Thalassaemia is also prevalent in Italy, and it was reported to have a high frequency of 38% in Sardinia . The most frequent mutation is α 3.7 deletion, and 89% of the α-thalassaemia patients were identified to be carriers of one or two of the most common α 3.7 , α –Med , α2 HphI , α2 NcoI and α1 NcoI thalassaemia 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 . Hb H disease is also more common with such genetic background. Spain also has high prevalence of α-thalassaemia; the allelic frequency is 1.4%–2.4%, and the mutation is mostly α 3.7 deletion . Other types of mutation are also observed: α 4.2 deletion is occasionally observed and α –Med and α –SEA deletion had also been reported.
In African countries, α-thalassaemia gene mutation is common. α 3.7 deletional thalassemia has a gene frequency of 0.21 in Nigeria. Northern Africa shares similar genotype frequency as other Mediterranean countries . A summary of the common α mutations is shown in Table 1 .
| Regions | Types | Mutation | Remarks |
|---|---|---|---|
| Southeast Asia | α 0 | – – SEA | Most common deletion among Asians and world wide |
| – – FIL | Mainly in Philippians | ||
| – – THAI | Common among Thai | ||
| α + | – α 3,7 | Relatively common | |
| – α 4,2 | 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, Laotians | ||
| α init A-G | Common in Vietnam | ||
| India | α + | – α 3,7 | Common |
| – α 4,2 | 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 | α 0 | – – MED I | Common in Iran, Arab population |
| α + | – α 3,7 | Common in Iran, Arab population | |
| α + – α 0 | α PA1 (AATAAG) | Relatively common in Arab population | |
| African, Afro-American and Afro-Caribbean | α 0 | – α 3,7 init GTG | One of the few α 0 -thal alleles in African population |
| – α 3,7 init (-2 bp) | One of the few α 0 -thal alleles in North-African population | ||
| α + | – α 3,7 | Common | |
| – α 3,7 Cd14 T>G | Hb Evanston, relatively rare | ||
| α Seal Rock | Relatively rare | ||
| Mediterranean | α 0 | – – 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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