Molecular Testing in Hemochromatosis

Abstract Hemochromatosis (HC) is a systemic iron overload disease of genetic origin. Its usual form, HFE -related HC, is one the most prevalent genetic diseases in the Caucasian population, but with partial penetrance. Genetic testing to demonstrate homozygosity for the C282Y ( p.Cys282YTyr ) mutation confirms the diagnosis in the individual patient and provides the foundation for a family study. In the context of documented body iron excess and absence of a homozygous C282Y mutation, the patient has either a rare form of HFE -related HC or non- HFE -related HC. Some of these non- HFE -related forms share the HFE HC phenotype due to hepcidin insufficiency, though often with a more severe expression. Most often, non- HFE forms of HC are associated with mutations of the hemojuvelin ( HJV ), hepcidin ( HAMP ), or transferrin receptor 2 ( TFR2 ) genes. Two other non-HFE forms of HC, that are related to deficient cellular iron egress, harbor mutations of the ferroportin ( SLC40A1 ) or ceruloplasmin ( CP ) genes. 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.