Scientific background:

Summary: Two mutations in this gene, encoding a putative iron transporter, have been associated with hemochromatosis.

Gene: The gene is about 10kb in size. It is located on chromosome 6 at position 6p21.3. There are 11 splice variants known at this moment. These consists of 3 to 7 exons.

Pathology: The protein product of this gene is responsible for iron uptake and removal by the enterocytes. The machanism of its function is not known yet. If this ene is mutated this leads to iron overload in liver, pancreas and heart.

Clinical signs: The clinical picture depends on the organ dysfunction when iron overloaded. In liver it causes zirrhosis, in pancread diabetes and in cardiac muscels heart failure. The colour of skin is typical in full blown disease. The diagnosis can be confirmed by histological investigation with iron staining.Interestingly mutations in this gene seem to be a risk factor for life.

Epidemiology: The frequency of homozygous C282Y mutations among patients with hemochromatosis is 52-100%. In our country it is about 90%. The remainder might be mixed heterozygous (C282Y/H63D) about 5%, homozygous (H63D) about 1,5%, heterozygous (C282Y) about 3,6% or heterozygous (H63D).In caucasian population homozygous C282Y mutation is about 0,4% and heterozygous 9,2%.Allelfrequency of H63D mutation is about 22% in Europe. The C282S mutation is extremely rare.

Interpretation: You can use this test to confirm the diagnosis.

Test strategy: Patients with clinical and biochemical findings suspect for hemochromatosis.

Methodology:

	clinical test	Method		Hotspot sequencing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal and in some aspects external quality control
	Only in the region of interest, known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Fragment analysis
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Full external quality control
	Only the target mutation is detected all other genetic variations, though possibly important they may be, are missed.

Literature: 

Hanson EH et al. (2001) HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology.
Lucotte G et al. () Frequency analysis and allele map in favor of the celtic origin of the C282Y mutation of hemochromatosis.
Bathum L et al. (2001) Association of mutations in the hemochromatosis gene with shorter life expectancy.
Bathum L et al. (2001) Association of mutations in the hemochromatosis gene with shorter life expectancy.