Haemochromatosis

Hereditary haemochromatosis (HH) is a recessively-inherited disorder, characterized by excessive absorption of dietary iron, prevalent in some northern European populations. If left untreated it can lead to morbidity and mortality, including liver cirrhosis, hepatocellular carcinoma, diabetes and heart disease. Early treatment by phlebotomy can help prevent complications (European Association For The Study Of The Liver 2010).

The most common and well-defined form of HH is HFE-related hereditary haemochromatosis, associated with homozygosity of the p.(Cys282Tyr) (c.845G>A) variant in the HFE gene. It has been estimated that 1 in 200-300 individuals with northern European ancestry are homozygous for p.(Cys282Tyr), however penetrance is low with only 15-25% of homozygotes developing disease (European Association For The Study Of The Liver 2010). Homozygosity for the p.(Cys282Tyr) variant is therefore not sufficient for a diagnosis of hereditary haemochromatosis and this has important implications for molecular genetic diagnostic practices.

Testing is not indicated in the following situations:

• Carrier testing asymptomatic parents of p.(Cys282Tyr) homozygotes
• Testing of relatives of p.(Cys282Tyr) heterozygotes
• Testing of relatives of p.(His63Asp) heterozygotes and homozygotes
• Testing of minors (<16 years)
• Prenatal diagnosis is not appropriate in HFE-related HH
• Population screening (screening of unaffected individuals with no family history) for the p.(Cys282Tyr) variant.

R95 Iron overload – hereditary haemochromatosis testing

Analysis of the HFE gene

Visit the NHS Genomic Test Directory 

Eligibility criteria for genomic tests can be found in the National Genomic Test Directory.

This lists the clinical specialties that would be expected to request for a given clinical indication and sets out which patients should be considered for testing.

In accordance with best practice guidelines, testing is only indicated in patients who meet the following criteria:

• Unexplained iron overload (with raised transferrin saturation and/or serum ferritin) suggestive of hereditary haemochromatosis. It should be noted that, although elevated serum ferritin is a potential biochemical marker of iron overload, it is not specific for HH, therefore elevated ferritin should ideally prompt transferrin saturation testing before genetic testing is requested.

Please note that Exeter Blood Sciences department only perform transferrin saturation measurements when iron studies are requested.

• Adult siblings (>16 years) and offspring of p.(Cys282Tyr) homozygotes. Please note that it is more cost-effective to offer carrier testing to partners of p.(Cys282Tyr) homozygotes prior to offering testing to two or more offspring.

All samples for genomic testing should be accompanied by a fully completed request form.

The request form should include as much clinical information about the patient or family member, family relationships and the requested test code (R number). All request forms must indicate either a specific disorder/gene(s) to be investigated or, a request to extract and store DNA.

This form should be used for the majority of test requests.

Please do not download and store this on your desktop or system. The form is regularly updated. Our recommendation is to save or bookmark a link to our website to ensure you are working with the most up-do-date version.

Download the latest version here: GMS Test Order Form v2.3

An appropriate discussion of genomic testing and the possible implications for a patient and their family members must take place before testing is requested.

It is the referring clinician’s responsibility to ensure that the patient/carer knows the purpose of the test and that the sample may be stored for future diagnostic testing. In submitting a sample with a request form, the clinician confirms that informed consent has been obtained for (a) testing and storage (indefinitely) (b) the use of this sample and the information generated from it to be shared with members of the donor’s family and their health professionals (if appropriate). The patient should be advised that the samples may be used anonymously for quality assurance and training purposes.

If stated as a requirement for a specific test, a record of this discussion must be retained within the patient record when a genomic test is ordered.

For more information please view the Consent and Confidentiality in Genomic Medicine guidelines from the Joint Committee on Medical Genetics.

Before sending samples for genomic testing, please ensure you follow the correct preparation and transport guidelines. This includes information on sample types, volumes, handling, labelling, and packaging standards.

For a full list of sample requirements and transport guidance, please visit the samples and transport page of the website. 

Turnaround times (TATs) for genomic tests are continually refined through ongoing reviews of testing standards.

Results will be returned to the email account or clinician listed on the request form.

Visit the results and turnaround page for more information.