While the condition is often associated with mutations in a single gene, particularly the HFE gene, recent clinical cases of digenic inheritance have been identified. 

What is Digenic Inheritance?

Digenic inheritance occurs when mutations in two different genes combine to cause a disease or modify its presentation. This is different from the more common monogenic inheritance, where a single gene mutation leads to the condition. In genetic haemochromatosis, digenic inheritance can involve mutations in the HFE gene as well as mutations in other genes involved in iron regulation.

Genes Involved in Haemochromatosis

The most well-known gene associated with haemochromatosis is the HFE gene, particularly the C282Y, H63D and S65C mutations. However, digenic forms of haemochromatosis can arise when mutations in another iron-regulating gene are present alongside HFE mutations. These genes may include:

• HJV (hemojuvelin gene): Associated with a more severe form of haemochromatosis, often seen in younger patients (juvenile haemochromatosis).
• TFR2 (transferrin receptor 2 gene): Linked to a milder form of the disease, but in combination with HFE mutations, it can lead to significant iron overload.
• HAMP (hepcidin antimicrobial peptide gene): Hepcidin is a key regulator of iron metabolism, and mutations in this gene can exacerbate iron accumulation.

How Does Digenic Inheritance Affect Genetic Haemochromatosis?

In individuals with digenic inheritance genetic haemochromatosis, the presence of mutations in two separate genes may result in:

• Earlier onset of symptoms: Compared to typical haemochromatosis, those with digenic inheritance might experience symptoms earlier, sometimes in adolescence.
• Increased severity: Iron overload may be more severe due to the combined effects of mutations in two genes involved in iron regulation.
• Challenges in diagnosis: Genetic testing may reveal mutations in multiple genes, complicating the understanding of the inheritance pattern and predicting disease progression.

Genetic Testing and Diagnosis

Diagnosis of digenic genetic haemochromatosis involves comprehensive genetic testing, looking for mutations in multiple genes involved in iron metabolism. Testing for the common HFE mutations, such as C282Y, H63D and S65C, is often the first step. However, if a patient presents with unusual symptoms or early onset, further testing for other genes like TFR2, HJV, and HAMP may be necessary.

Treatment of Genetic Haemochromatosis with Digenic Inheritance

The treatment for digenic haemochromatosis is similar to that for monogenic forms, but it may need to be tailored depending on the severity of iron overload. The primary treatment is phlebotomy (regular blood removal) to reduce iron levels. In severe cases, iron chelation therapy may be considered.

Ongoing monitoring of liver function, heart health, and blood sugar levels is critical, as iron overload can continue to damage these organs if not effectively managed.

If you or a family member has been diagnosed with haemochromatosis, genetic counselling and comprehensive testing can help uncover potential digenic inheritance patterns and guide treatment.