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• The haemoglobin protein, found in red blood cells, transports oxygen from the lungs to all parts of the body and gives blood its red colour. In adults, the haemoglobin protein is made up of four 'protein chains': the 'alpha (α) globin chain' and 'beta (β) globin chain'. There are usually two alpha globin chains and two beta globin chains
• A number of different genetic conditions are due to inheriting one or more faulty copies of the gene(s) that contain the information for the cells to make the globin protein chains
• The faulty genes may result in an abnormality in the production or structure of the haemoglobin protein causing a group of conditions that include alpha (α) thalassaemia, beta (β) thalassaemia and sickle cell disease
• Alpha thalassaemia major is caused by absent production of the alpha-globin chains in the haemoglobin protein due to having no copies of the alpha-globin chain genes. This condition, also known as Hb Barts hydrops fetalis is fatal at or around the time of birth
• Beta thalassaemia major is caused by reduced or absent production of the beta-globin chain of the haemoglobin due to having a loss (deletion) or a change in both copies of the beta globin chain gene. The main symptom is severe anaemia requiring life-long blood transfusions
• Sickle cell disease is caused by changes in the structure of the beta-globin chains of haemoglobin, resulting in red blood cells that form an irreversible sickle shape and leading to severe anaemia and other problems
• Genetic carriers for these conditions may have mild anaemia, but usually have good health and their bodies function normally
• At least 1 in 20 adults are genetic carriers for a haemoglobin condition, but the chance is higher for
• Alpha thalassaemia if their ancestry is from China and South East Asia, Southern European countries, the Middle East, the Indian Subcontinent, Pakistan, Africa, the Pacific Islands and New Zealand (Maori)
• Beta thalassaemia if their ancestry is from the Middle East, Southern Europe, Indian Subcontinent, Central and South East Asia and Africa
• Sickle cell disease if their ancestry is from Africa, the Middle East, Southern Europe, India, Pakistan, South America and the Caribbean
• The pattern of inheritance in families of the faulty gene(s) causing these conditions is described as autosomal recessive inheritance
• A blood test can determine if an individual is a genetic carrier and is appropriate for people when there is a family history, a blood relative is a genetic carrier or according to their ancestry
• Genetic testing may be available in pregnancy if both parents are carriers of a faulty haemoglobin gene

The cells of the body contain information, in the form of genes, for the body to make all the necessary structural components and chemicals to ensure normal function (see Genetics Fact Sheet 1).

If a gene is changed so that it does not work properly, it is described as being faulty. The information contained in the faulty gene, and its product, is impaired (see Genetics Fact Sheets 4 & 5).

In adults, the haemoglobin protein is made up of four sub-units that are joined together: these sub-units are referred to as 'protein chains'. There are two types of these protein chains: one that is called the 'alpha (α) globin chain' and one that is called the 'beta (β) globin chain'. The haemoglobin protein is usually made up of two alpha globin chains and two beta globin chains.

The genetic information for the body to make the two different haemoglobin chains is contained in two different haemoglobin genes located on two different chromosomes:

• Two identical α-globin genes code for the α globin chains located on chromosome number 16
• The β-globin gene codes for the beta β globin chain located on chromosome number 11

There are two copies of each of these chromosomes in every body cell.

Everyone therefore has four copies of the alpha globin gene and two copies of the beta globin gene in their body cells

Inherited changes that make the alpha or beta globin genes faulty or where the genes are missing (deleted) can lead to haemoglobinopathy conditions.

The World Health Organization (WHO) estimates that globally at least 5% of adults are genetic carriers for a haemoglobin condition:

• About 2.9% for thalassaemias
• About 2.3% for sickle cell disease

The chance of being a genetic carrier for a haemoglobin condition is influenced by the person's ancestry (see below). Some population groups are more likely to be a genetic carrier for a haemoglobin condition than others. Most countries have an uneven distribution of genetic carriers in their population because the population is made up of people with different ancestries.

In thalassaemia, one of the haemoglobin chains is either missing, produced in greatly reduced amounts, or has an abnormal structure. As a result, the haemoglobin in the red blood cells of people affected with thalassaemia, does not function normally.

There are two different types of thalassaemia based on which of the globin chains are affected.

• Alpha (α) thalassaemia
• Beta (β) thalassaemia

In some cases, an individual can be a genetic carrier for both alpha and beta thalassaemia. Nevertheless, they are no more severely affected than if they were a genetic carrier for one type of thalassaemia only.

Alpha (α) thalassaemia

There are two pairs of alpha thalassaemia gene copies (a total of four gene copies). Alpha thalassaemia occurs when one or more of the four alpha globin gene copies are faulty. There are four different types of alpha thalassaemia depending on how many of the four alpha globin gene copies are faulty. Two types of alpha thalassaemia are known as carrier states and are not associated with any significant health problems. The other two types of alpha thalassaemia are associated with significant health problems.

Carrier states of alpha thalassaemia

• When only one of the four alpha globin gene copies is faulty there is only a small reduction in the amount of alpha globin protein produced by the body. This type of thalassaemia does not cause any health problems. A person with this condition is known as a silent carrier because this type of alpha thalassaemia is not usually detectable by a routine blood test
• When two of the four alpha globin gene copies are faulty the body produces less alpha globin protein. Individuals with this are generally healthy but may have smaller red blood cells and at worst may have some mild anaemia. This type of thalassaemia is usually detectable on a routine blood test. The two alpha globin gene faults can occur on the same chromosome (alpha zero trait) or on one of each of the chromosome pair (alpha plus trait)

Affected states of alpha thalassaemia

• If three of the four alpha globin gene copies are faulty, this may cause a significant health problem. Individuals with this condition have lifelong anaemia that may require treatment with blood transfusions. This condition is an intermediate form of alpha thalassaemia and is also known as haemoglobin H disease or HbH disease
• When all four of the alpha globin gene copies are faulty this results in a severe form of alpha thalassaemia where babies with the condition usually do not survive long after birth. This is because no alpha globin protein is produced and there is build up of an abnormal haemoglobin protein. This condition is also know as Hb Barts hydrops fetalis

The different alpha thalassaemias and the gene changes that result in each form of alpha thalassaemia are shown in Figure 34.3a.

Beta (β) Thalassaemia

There are only two gene copies for beta thalassaemia (one on each chromosome). Beta thalassaemia exists in two states, either as a carrier, (beta thalassaemia minor), or affected (beta thalassaemia major).

Beta (β) thalassaemia minor

Beta thalassaemia minor (also known as beta thalassaemia trait) is a condition caused by one of the two beta globin gene copies being faulty. Individuals with this condition are generally healthy, but may have smaller red blood cells and may have mild anaemia. They are carriers for beta thalassaemia.

Beta (β) thalassaemia major

This form of the condition is

• Also known as Cooley anaemia
• Evident after birth, usually within 6 to 12 months
• A condition in which the main symptom is severe anaemia (a blood condition that makes people tired and pale: not enough oxygen is available to the cells)
  • The anaemia develops during the first few years of life and frequent blood transfusions must be given to maintain the life of a person who has this type of thalassaemia
  • Since iron is an important part of the haemoglobin protein, the transfusions cause a build-up of iron in the person's heart, liver and other organs. Special treatment is necessary to remove the iron
  • Other features include pallor, lethargy, poor appetite, developmental delay, failure to thrive, growth failure with bone changes and fractures
• Caused by reduced or absent production of the beta-globin chain of the haemoglobin due to having a loss (deletion) or a change in both copies of the beta globin chain gene
• More common in people whose ancestry is from the Middle East, Southern Europe, Indian Subcontinent, Central and South East Asia and Africa

While being a carrier for thalassaemia or sickle cell disease may cause a mild anaemia, genetic carriers usually have good health and their bodies function normally. Genetic carriers for sickle cell disease however, may also have problems when having an anaesthetic, the result being that the red blood cells of a carrier can undergo 'sickling'.

The chance of being a genetic carrier for one of these conditions depends on an individual's ancestry. The chance of being a carrier is higher in people of certain backgrounds.

• For alpha thalassaemia: China and South East Asia, Southern European countries, the Middle East, the Indian Subcontinent, Pakistan, Africa, the Pacific Islands or New Zealand (Maori)
• For beta thalassaemia: the Middle East, Southern Europe, Indian Subcontinent, Central and South East Asia or Africa
• For sickle cell disease the risk is high if an individual's ancestry is from Africa, the Middle East, Southern Europe, India, Pakistan, South America or the Caribbean

There are several theories as to why the frequency of the condition, and the number of genetic carriers for thalassaemia, is high in these populations.

• Once a mutation occurs in the haemoglobin chain gene of an egg or sperm cell, it is passed down through the generations of a family
• Geographic barriers would have meant that people from close villages who had the faulty gene would marry and this would have kept the mutation in the haemoglobin chain gene within the local populations. There would be a higher chance of both parents being genetic carriers for one of the types of thalassaemia and therefore the number of children born with thalassaemia, and genetic carriers for thalassaemia would increase
• It is thought that being a genetic carrier for thalassaemia provides protection against malaria, a mosquito-borne disease. Throughout history, those who were genetic carriers for thalassaemia would have had a better chance of surviving malaria and have children of their own

Haemoglobin conditions are genetic conditions (see Genetics Fact Sheet 2). Therefore they are passed from parents to children in their genes.

Two factors influence the pattern of inheritance of the faulty globin genes causing beta thalassaemia or sickle cell disease in families.

1. These particular globin genes are located on chromosome 11 which is an autosome (a numbered chromosome)
2. The effect of the change in the gene is 'recessive' or hidden by the presence of the working copy of the gene (see Genetics Fact Sheets 1, 4 & 5)

The pattern of inheritance of the faulty or missing haemoglobin gene in families is therefore described as autosomal recessive inheritance (see Genetics Fact Sheet 8).

In Figures 34.1a&b and 34.2a&b which illustrate the pattern of inheritance, the faulty globin gene copy is represented by 'r'; the working copy by 'R'. There are four possibilities, in every pregnancy, for the combinations of the genes passed from the parents.

As shown in Figures 34.1a and 34.1b, if a couple who are both carriers of the faulty, or missing globin gene have a baby, in every pregnancy there is a

• 1 in 4 chance, or 25%, that they will have a child who inherits both copies of the faulty gene from his/her parents. In this case, no working gene product will be produced and their child will be affected by the haemoglobin condition
• 1 in 4 chance, or 25%, that their child will inherit both copies of the working gene and will be unaffected by the haemoglobin condition and cannot pass the faulty gene on to their children
• 1 in 2 chance (2 in 4 chances), or 50%, that their child will inherit one faulty copy of the gene and one working copy of the gene from each parent and he/she will be an unaffected genetic carrier for the haemoglobin condition, just like the parents

Figure 34.1a: Autosomal recessive inheritance where both parents are carriers of the faulty beta globin gene copy with one chance in four of having a child with beta thalassaemia major. The faulty haemoglobin chain gene copy is represented by 'r'; the working copy by 'R'.

Figure 34.1b: Autosomal recessive inheritance where both parents are carriers of the faulty beta globin gene copy, with one chance in four of having a child with sickle cell disease. The faulty beta haemoglobin chain gene copy is represented by 'r'; the working copy by 'R'.

As shown in Figures 34.2a and34.2b, if only one parent is found to be a carrier of the faulty or missing globin gene, in every pregnancy

• It is very unlikely that the couple will have a baby affected with the particular haemoglobin condition
• There is a 1 chance in 2 (ie. 2 chances in 4) or 50% that the baby will be an unaffected genetic carrier for the haemoglobin condition, just like his/her parents

Figure 34.2a: Where only one parent is a carrier of the faulty beta globin gene copy
and there is no chance of having a child with beta thalassaemia major.
The faulty haemoglobin chain gene copy is represented by 'r'; the correct copy by R.

Figure 34.2b: Where only one parent is a carrier of the faulty beta globin gene copy and there is no chance of having a child with sickle cell disease. The faulty betaglobin chain gene copy is represented by 'r'; the working copy by 'R'.

How does a person inherit alpha thalassaemia?

Alpha thalassaemia is a genetic condition (see Genetics Fact Sheet 2). It is therefore passed down from parents to children in their genes.

Two factors influence the pattern of inheritance of the faulty globin genes causing alpha thalassaemia.

1. These particular globin genes are located on chromosome 16, which is an autosome (a numbered chromosome)
2. The effect of the change in the gene is 'recessive' or hidden by the presence of a working copy of the gene (see Genetics Fact Sheets 1, 4, & 5)

The pattern of inheritance of the faulty or missing haemoglobin gene(s) in families is therefore described as autosomal recessive inheritance (see Genetics Fact Sheet 8).

The inheritance of alpha thalassaemia is complicated, however, by there being four alpha globin gene copies. Figures 34.3a and b illustrate the different possible alpha thalassaemias including carriers for alpha thalassaemia and those who are affected with alpha thalassaemia. An example of a family where parents are carriers for alpha thalassaemia, illustrating the chance of them passing on specific combinations of faulty alpha thalassaemia gene copies to their children, is also shown. In this example, there is a possibility that the parents may have a child with the most severe form of alpha thalassaemia, Hb Barts hydrops fetalis.

Figure 34.3a: The different possible carrier states for alpha thalassaemia (silent carrier, alpha zero trait
and alpha plus trait) and affected states (HbH disease and Hb Barts hydrops fetalis) are shown in this figure.
The faulty alpha globin gene copies are indicated by a minus sign (-) and working copies of the gene by 'a'.

It is important to note that not all the possibilities for carrier parents for alpha thalassaemia have been outlined, and the parents shown in Figure 34.3b are only one such possibility.

Figure 34.3b: Autosomal recessive inheritance where both parents are carriers of two faulty alpha globin
gene copies (alpha zero trait). There is one chance in four of having a child with a severe form of alpha
thalassaemia major, Hb Barts hydrops fetalis. The faulty alpha globin gene copies are indicated by a
minus sign (-) and working copies of the gene by 'a'.

How can people find out if they are genetic carriers for thalassaemia or sickle cell disease?

A blood test can determine if an individual has a type of alpha thalassaemia trait or has sickle cell trait and is therefore a carrier of the faulty gene involved in that type of haemoglobin condition.

• Even though some of the red blood cells in people with thalassaemia minor or sickle cell trait are abnormal compared to non-carriers, their blood still enables normal body function

There is an increased chance that someone is a carrier of a faulty gene involved in these conditions if they have a family history of the condition or a blood relative who is known to be a genetic carrier for the condition.

Genetic testing to determine the type of change making the gene faulty that is running in the family may be available and can be discussed with their doctor or a genetic counsellor (see Genetics Fact Sheet 3).

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Berdoukas, V. (1997). Haemoglobinopathies: how much should the GP know? Modern Medicine of Australia, March, 126-34

Bowden, DK. (2001). Screening for thalassaemia. Australian Prescriber, 24:120-23

Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD) [online].Available from: http://www.ncbi.nlm.nih.gov/omim/. [Accessed June 2007]

National Organisation for Rare Disorders (NORD) [online]. Available from: http://www.rarediseases.org/ [Accessed June 2007]

Trent R et al. (2006). Complex phenotypes in the haemoglobinopathies: recommendations on screening and DNA testing. Pathology, 38: 507-19