How is haemochromatosis inherited?

Genetic haemochromatosis, as its name suggests, runs in families and is now recognised as one of the most common disorders of this type.

The disorder is caused by a gene. This is a segment of DNA containing the instructions for making up your body. Genes are packaged in a sequence on strands of DNA called chromosomes which are found in the nucleus of your body cells. All of us carry up to 30,000 individual genes.

All of your body cells should contain a gene inherited from your mother and one from your father. We generally carry the same genes as each other, but around 1% of genes will differ between people. These small differences are what contribute to each person’s unique physical traits. 

The HFE gene mutation
Genes are responsible for managing the production of proteins that control the cells in your body.

The HFE gene contains instructions for producing a protein that helps with the digestion of food by managing the absorption of iron into your small intestine. When functioning normally this mechanism limits the amount of iron going into your body from your diet.

In 1996 changes in the HFE gene were found to be associated with haemochromatosis. A permanent change in the code of the DNA making up a gene or chromosome is known as a ‘mutation’. This can alter the way a physical characteristic is expressed or cause some function in the body to occur differently. Sometimes the word ‘variant’ is used instead as many changes do not cause any disorder.

It is thought that mutations on the HFE gene restrict its ability to control iron intake. This is linked to a deficit of hepcidin, a peptide or small protein responsible for regulating iron in your body.

There are actually two known common variants in the HFE gene that have been associated with iron overload. These are called C282Y and H63D. The numbers 282 and 63 indicate where the mutations are found on the HFE gene. The mutations occur on a specific chromosome (chromosome six).

The C282Y mutation is the more severe. It is found only among people of northern European origin and may date back several thousand years. In the UK about one in eight people carry one copy of the HFE gene with the C282Y mutation but such ‘carriers’ are not at risk from iron overload.

The H63D variant is associated with a milder disease and usually only when inherited with a copy of the HFE gene having the C282Y mutation. It is thought to be much older and is spread more widely throughout the world. In the UK one in four people carry one copy of the HFE gene with the H63D variant. They are not at risk from iron overload.

In the UK about 90% of people with haemochromatosis have two copies of the C282Y mutation. About 5% have one copy of each mutation (C282Y/H63D) and the remainder have only one copy of the C282Y or H63D variants or no copies. These people may have other changes in the HFE gene or changes in other genes causing iron overload.

Not all people with haemochromatosis will therefore have typical gene mutations.
To develop haemochromatosis that is linked to the HFE gene, both copies of the gene must be
affected. For this reason it is known as a ‘recessive’ disorder, as opposed to a ‘dominant’ disorder where only one gene is required.

In over 90% of people diagnosed with the disorder, both genes have been found to be abnormal.
A person who has only one abnormal gene is known as a ‘carrier’. They are not usually affected but can pass on the gene to their own children. On average, half the eggs or half the sperm of a
carrier will contain the abnormal gene.

A person who inherits the mutation from both parents will carry the abnormal gene in all of their
eggs and sperm.

People who inherit the same mutated gene from both of their parents (e.g. C282Y/C282Y) are termed ‘homozygote’. Those who inherit one mutated gene only (carriers) are called ‘heterozygote’. People who have two different forms of the mutated gene are called ‘compound heterozygotes’.

Scientists still have some way to go to be able to answer important questions about how genetic haemochromatosis occurs. It is still not known how many people with the defective HFE gene will go on to develop symptoms or why some people develop symptoms and others do not.

However, using data based on the whole population it has been possible to work out the theoretical chance of a person inheriting the abnormal gene when one or both of their parents have it.


Download: The above diagram Final GH diagram.pdf

When both parents are carriers for the abnormal gene there is a 25% chance of a child being homozygote. On average, 50% of the children from this relationship will be carriers and 25% will be normal.

Where one parent is homozygote for the gene and the other is a carrier, 50% of the children will be homozygote and 50% will be carriers.

If one parent is homozygote and the other is unaffected, all of their children will be carriers.

In the rarest case, where both parents are homozygote, all of their children will also be homozygote and will be at risk of developing haemochromatosis.