Gene penetrance
The difference between the number of people having the gene variants (the genotype) and the condition (the phenotype) is known as ‘penetrance’. (This may make more sense if you think of it as how much the disease breaks through – or penetrates.)
Very few genetic conditions have 100% penetrance – most have ‘incomplete penetrance’, including haemochromatosis. With incomplete penetrance, doctors can’t predict who will develop the actual condition and who won’t.
Doctors don’t fully understand what affects gene penetrance. It’s likely to be a mix between other genes that influence the same processes in the body and things in your daily life (environmental factors).
In the case of haemochromatosis, there are several other genes that help to control how your body takes in and uses iron (iron metabolism). These genes may take over all or part of this job in some people who have a haemochromatosis genotype.
Thinking of environmental influences, haemochromatosis may be affected by how much iron there is in people’s diets. Or by other things that affect the liver, such as alcohol or other liver toxins. Having said that, there is currently little or no evidence that diet or alcohol have any effect in haemochromatosis penetrance. We just don’t know for sure what does cause some people to develop haemochromatosis when others with the same genetic make-up don’t.
If I have the gene variants, what are the chances I’ll have iron overload?
Doctors don’t know for sure. We do know that you’re more likely to develop haemochromatosis as you get older. And that the chances are higher in men than in women. But different research studies have come up with different figures.
You can think about this in 3 levels:
- Some people with the necessary gene variants have no sign of haemochromatosis at all.
- Some people have signs of haemochromatosis in blood tests. This means that blood tests are showing that their iron levels are beginning to rise. But they have no other signs or symptoms of haemochromatosis. Doctors call this ‘biochemical penetrance’.
- Other people have biochemical penetrance and also have symptoms of iron build up in the body. Doctors call this clinical penetrance.
If you have the gene variant for haemochromatosis on both copies of the gene, you will need to have regular blood tests throughout your life to check for iron building up (iron overload).
Having signs in your blood tests (biochemical penetrance)
It’s likely that at least half of those with haemochromatosis gene variants will have signs of haemochromatosis in blood tests at some point. This may be up to 8 out of 10 men (80%). It’s less common for women, with just over half (55%) developing these signs. It’s lower for women because they lose iron each month when they bleed during a period. This naturally lowers their iron levels until they reach menopause.
If your blood tests are showing signs of biochemical penetrance, your doctor will continue to monitor you. But they may not suggest treatment if there is no sign that the amount of iron stored in your body is too high.
Having symptoms of iron build up in your body (clinical penetrance).
If you have iron build up, your doctor may call this ‘iron overload’. If you have signs of iron overload in your blood tests it will mean you need to start treatment. Your doctor will also monitor you for symptoms.
Actually having symptoms of iron overload is much less common than showing signs in a blood test. Most people with haemochromatosis genes will never develop any clinical signs or symptoms other than possibly fatigue and joint pain (which are relatively common). As with signs in your blood tests, it’s more common for men to have symptoms, and as you get older.
Published: September 2025
Review date: September 2028
Clinical reviewers: Jeremy Shearman, Consultant Hepatologist and Gastroenterologist, South Warwickshire University Foundation Trust. Sister Kim Hicks, Medical Day Unit Haemochromatosis Nurse, Royal Cornwall Hospital, Treliske. Dr Indra van Mourik, Consultant Paediatric Hepatologist (retired).
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