Chapter 20 - Molecular testing in hemochromatosis

Abstract

Hemochromatosis (HC) is a systemic iron overload disease of genetic origin. Its commonest form, HFE-related HC, is one the most prevalent genetic diseases in the Caucasian population, but with variable penetrance and expression. In the context of documented high transferrin saturation, serum ferritin (SF), and body iron excess, genetic testing revealing homozygosity for the p.Cys282YTyr mutation confirms the diagnosis in the individual patient and provides the foundation for a family study. In case of very low penetrant genotypes (e.g., compound heterozygosity for p.Cys282Tyr/p.His63Asp and p.His63Asp homozygosity), assessment of coexistent disorders that can increase SF and/or favor iron overload is needed. Quantitation of liver iron by magnetic resonance imaging is useful to definitely assess iron overload and adequate therapy. If there is only heterozygosity for p.Cys282Tyr, specializing centers should perform HFE sequencing to search for rare compound heterozygosity. In case of non-at-risk HFE genotypes, the patient might have a rare non-HFE-related HC. Some of these non-HFE-related forms share the HFE-HC phenotype due to hepcidin insufficiency (biallelic mutations in HJV, HAMP, and TFR2) or ferroportin resistance to hepcidin (gain-of-function mutations of SLC40A1) with similar or more severe expression (juvenile HC). In rare HFE and non-HFE-HC, molecular testing performed by specialty laboratories is critical, not only for diagnosis of the individual patient, but also for family screening. Next-generation sequencing is radically changing the technological face of molecular diagnosis of HC, bringing obvious benefits, but also raising important medical and ethical issues.