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Genotype–Phenotype Relationship in Hereditary Hemochromatosis

  1. Lachlan RO Ayres,
  2. Vanoo Jayasekeran,
  3. John K Olynyk

Published Online: 8 DEC 2013

DOI: 10.1002/9780470015902.a0024259



How to Cite

Ayres, L. R., Jayasekeran, V. and Olynyk, J. K. 2013. Genotype–Phenotype Relationship in Hereditary Hemochromatosis. eLS. .

Author Information

  1. Fremantle Hospital, Fremantle, Australia

Publication History

  1. Published Online: 8 DEC 2013


The majority of patients of northern European descent with hereditary hemochromatosis are homozygous for the C282Y mutation in the HFE gene product. A significant proportion of patients with this genotype have elevated iron indices; however, most will not develop symptoms or organ damage. Age, gender and alcohol are the key factors known to influence this wide variation in clinical penetrance. The authors describe the three stages of disease ranging from only genetic abnormality to overt disease and review the other factors that modify the genotype–phenotype relationship. Algorithms for use in clinical practice are included to aid clinicians in diagnosis, risk stratification and treatment.

Key Concepts:

  • Mutations in the HFE gene are relatively common.

  • The vast majority of patients with iron overload are homozygous for the C282Y mutation in the HFE gene product.

  • Biochemical penetrance, that is, elevated iron stores are present in 70–91% of males and 30–60% of females who are C282Y homozygotes.

  • End-organ damage is less common and occurs in approximately one-quarter of males and 1% of females.

  • End-organ damage is extremely unlikely if serum ferritin is less than 1000 µg l−1.

  • The principal modifiers of disease are gender, age and alcohol. The wide variation in expression of clinical disease is largely unexplained.

  • Various genes have been shown to have variable modifying effects on disease penetrance.

  • Phlebotomy is a safe and effective treatment that depletes iron stores, prevents end-organ damage and confers normal life expectancy. It is best initiated on discovery of elevated iron stores, that is, stage-II or stage-III disease.


  • hereditary hemochromatosis;
  • genotype;
  • phenotype;
  • HFE;
  • C282Y;
  • clinical penetrance;
  • iron overload;
  • ferritin;
  • phlebotomy;
  • cirrhosis