Hemochromatosis: genetic testing and clinical practice

Area of Science:

• Genetics
• Molecular Biology
• Internal Medicine

Background:

• Hemochromatosis treatment necessitates early diagnosis of iron overload syndromes.
• Genetic testing aids in identifying at-risk individuals before pathological iron storage.
• Recent discoveries link numerous iron homeostasis proteins and their gene defects to iron storage disorders.

Purpose of the Study:

• To review the genetic landscape of hereditary iron overload disorders.
• To highlight the increasing prevalence of non-HFE related hemochromatosis.
• To discuss the polygenic nature and environmental influences on hemochromatosis expression.

Main Methods:

• Literature review of genetic causes of hemochromatosis.
• Analysis of gene mutations associated with iron storage.
• Examination of the role of HFE, FPN1, TFR2, HFE2, and HAMP genes.

Main Results:

• While HFE gene mutations (C282Y homozygosity) are common in adults, non-HFE genotypes are increasingly identified.
• Ferroportin 1 (FPN1) gene mutations are the second most frequent genetic cause in adults, primarily affecting macrophages.
• Rare defects in transferrin receptor 2 (TFR2) and mutations in hemojuvelin (HFE2) and hepcidin (HAMP) genes are associated with "non-HFE hemochromatosis" and juvenile hemochromatosis, respectively.
• Heterozygosity for HFE2 and HAMP mutations can modulate clinical presentation in adult-onset iron storage.

Conclusions:

• Hemochromatosis is increasingly recognized as a polygenic disorder influenced by environmental factors.
• Understanding iron pathophysiology is vital for integrating genetic testing into clinical decision-making.
• Genetic heterogeneity underscores the complexity of diagnosing and managing iron overload syndromes.