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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.

The Exeter Genomic Laboratory follows the guidelines suggested by the EMQN (click here for current EMQN best practice guidelines) and diagnostic eligibility criteria for test indication ‘R95 Iron overload – hereditary haemochromatosis testing’ as stated in the National Genomic Test Directory (NHS England » National genomic test directory).

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.

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.

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