Haemochromatosis revisited

Table 3 New classification of haemochromatosis proposed by the working group

New classification	Molecular pattern	Note
HFE-related	p.Cys282Tyr homozygosity or compound heterozygosity of p.Cys282Tyr with other rare HFE pathogenic variants or HFEdeletion.	Low penetrance; consider presence of host-related or environmental cofactors for iron overload. In subjects with other HFE genotypes (p.Cys282Tyr/His63Asp compound heterozygosity or p.His63Asp homozygosity) consider second-line genetic testing for rarer variants.
Non HFE-related	Rare pathogenic variants in non-HFE genes: - HJV-related; - HAMP-related; - TFR2-related; - SLC40A1 (very rare gain-of-function variant)-related.	Potentially, variants in any hepcidin-regulatory gene may be causative (the effects of novel mutations should be confirmed through functional and epidemiological studies). Molecular subtypes characterization only at specialized canters, but diagnosis of non-HFE related haemochromatosis is sufficient to start phlebotomies at nonspecialized centres1.
Digenic2	Double heterozygosity and/or double homozygosity/heterozygosity for variants in two different genes involved in iron metabolism (HFE and/or non-HFE).	More commonly, p.Cys282Tyr variants in HFE gene might coexist with variants in other genes; rarely, both variants involve non-HFE genes.
Molecularly undefined	Molecular characterization (still) not available after sequencing of known genes (provisional diagnosis).	Patients should be referred (or DNA should be sent) to specialized centers.

¹Providing that iron overload is confirmed by magnetic resonance imaging (MRI). If MRI is not accessible, close monitoring of haemoglobin level is needed to avoid occurrence of anaemia.

²Caution is needed to interpret as digenic inheritance results from next generation sequencing outputs reporting several variants in gene panels. Whenever possible, strict criteria for defining pathogenic variants should be adopted, and corroborated by family segregation and/or functional studies.