The number of new genes implicated in
iron metabolism has dramatically increased during the last few years. Alterations of these genes may cause
hyperferritinemia associated or not with
iron overload. Correct assignment of the specific disorder of
iron metabolism requires the identification of the causative gene mutation. Here, we propose a rational strategy that allows targeting the gene(s) to be screened for a diagnostic purpose. This strategy relies on the age of onset of the disease, the type of clinical symptoms, the biochemical profile (elevated or normal serum
transferrin saturation (TfSat)), the presence or not of visceral
iron excess, and the mode of inheritance (autosomal recessive or dominant). Then, two main entities can be differentiated: genetic (adult or
juvenile) hemochromatosis characterized by elevated TfSat, and hereditary
hyperferritinemias where TfSat is normal (or only slightly modified). Adult
genetic hemochromatosis (GH) is related mainly to mutations of the HFE gene, and exceptionally to mutations of the TFR2 gene. Juvenile GH is a rare condition related principally to mutations of the HJV gene coding for hemojuvelin, and rarely to mutations of the HAMP gene coding for
hepcidin. Hereditary
hyperferritinemias are linked to mutations of three genes: the
L-ferritin gene responsible for the
hereditary hyperferritinemia cataract syndrome (without
iron overload), the
ferroportin gene leading to a dominant form of
iron overload, and the
ceruloplasmin (CP) gene corresponding to an
iron overload syndrome with neurological symptoms. The proposed strategic approach may change with the identification of other genes involved in
iron metabolism.