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FeedbackPolymerase Chain Reaction/Fluorescence Monitoring
Hereditary hemochromatosis (HH) is a common genetic disorder that is most prevalent in adult males of northern European descent. The most common form of adult HH has been linked to variants (C282Y, H63D, and S65C) of the HFE gene, which codes for a protein responsible for iron regulation. Allele frequency varies by ethnicity. The severity of the causative variant correlates with the time course of iron overload and organ damage; more severe variants lead to pediatric onset of symptoms, while less severe variants may lead to adult symptom onset or may never result in symptoms. If left untreated, HH may lead to liver disease, skin hyperpigmentation, diabetes mellitus, or heart disease.
Genetics
Variants
HFE
- p.C282Y (c.845G>A)
- p.H63D (c.187C>G)
- p.S65C (c.193A>T)
Etiology
Pathogenic variants in the HFE gene result in increased iron absorption even in cases of normal dietary iron intake. HFE variants may lead to a high rate of iron absorption across duodenal enterocytes and/or excessive parenchymal storage of iron with end-organ damage.
Inheritance
Autosomal recessive
Test Interpretation
Clinical Sensitivity
Up to 90% for White populations, lower in other ethnicities
Analytic Sensitivity/Specificity
99%
Results
| Variant | Patient Presentation for Clinical and Biochemical Evidence of Iron Overload | Comments |
|---|---|---|
|
C282Y, H63D, S65C heterozygosity; H63D homozygosity |
May have elevated serum iron levels Positive clinical symptoms only if an additional rare, undetected HFE variant is present |
Negative clinical symptoms of iron overload Consider HFE or other alternative full gene sequencing and possibly deletion/duplication analysis if suspicion for HH remains high |
|
C282Y homozygosity |
Negative |
High risk for iron overload Only a minority develop clinical symptoms |
|
Positive |
Confirms diagnosis of HH Only a minority develop clinical symptoms |
|
|
C282Y/H63D; C282Y/S65C compound heterozygosity |
Negative |
Moderate risk of iron overload <2% risk of developing clinical symptoms |
|
Positive |
Supports a diagnosis of HH Penetrance is low: only a minority develop clinical symptoms |
Limitations
- Lack of detection of one of three HFE variants does not eliminate the possibility of HH
- Rare HFE variants and those in other iron-related genes are not detected by this test
- Rare diagnostic errors may occur due to primer-site variations
- Genotyping does not substitute for serum iron studies, which identify iron overload
References
-
GeneReviews - HFE Hemochromatosis
Barton JC, Edwards CQ. HFE hemochromatosis. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washingto, Seattle. Last update Dec 2018; accessed Feb 2020.
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Bacon BR, Adams PC, Kowdley KV , et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54(1):328-343.
31335359
Kowdley KV, Brown KE, Ahn J, et al. ACG clinical guideline: hereditary hemochromatosis. Am J Gastroenterol. 2019;114(8):1202-1218.
Use to confirm clinical diagnosis of HH in an individual with biochemical findings of iron overload, to screen adult family members of individuals with known HH, or to test the reproductive partner of an individual with HH for carrier status. Not recommended for initial hemochromatosis testing.