A genetic diagnostic service is provided to identify DNA changes in the HFE gene which are associated with an increased risk of developing HH. Identification of these changes facilitates the diagnosis and clinical management of at risk individuals, including family studies.
HH, an autosomal recessive adult onset disorder, is marked by increased plasma transferrin saturation associated with defective synthesis and / or regulation of hepcidin. Genes involved include HFE, HFE2, TFR2 and HAMP. HFE-related HH is by far the most common form of the disorder.
Patients with suspected iron overload should have fasting transferrin saturation and serum ferritin measurements. Normal serum ferritin essentially rules out iron overload, except in very rare cases of non HFE related HH. Raised serum ferritin levels have low specificity. HFE genotyping is indicated only if transferrin saturation is increased.
About 80% of Europeans with clinical iron overload are homozygous for the HFE C282Y variant (p.Cys282Tyr). When iron stores are elevated, with or without clinical symptoms, C282Y homozygosity is required for a diagnosis of HFE-HH. Any other HFE genotype should be interpreted with caution. Homozygosity alone for C282Y is not sufficient to diagnose HH – about 1 in 250 Caucasians in the general population have this genotype.
C282Y homozygotes are likely to develop increased serum ferritin and transferrin saturation, however only about 15 to 20% of individuals with this genotype go on to show clinical symptoms of iron overload. HH penetrance in C282Y homozygotes is higher in men than in women. Environmental factors such as alcohol misuse, steatosis and viral infections play key roles in the development of clinical symptoms.
The risk to develop iron overload in the future is increased in asymptomatic adult first degree relatives of C282Y homozygous index cases. Genotyping for C282Y, in association with genetic counselling, is recommended in such relatives in order to inform their future risk to develop iron overload.
The predicted heterozygous carrier rate for C282Y in the general population is approximately 10%. C282Y heterozygotes, including those in families where a diagnosis of iron overload has been made, are at very low risk of developing HH and genotyping of their first degree relatives is not recommended.
Hereditary haemochromatosis associated with the C282Y HFE gene mutation is a late-onset disorder of low clinical penetrance. Our policy, in accordance with extant national guidance, is not to perform genetic testing in children until they are old enough to make their own informed decision about such testing, unless test results will have a direct bearing on current clinical management.
(Last reviewed October 2018)