Table 4.

New classification of HC proposed by the working group

Novel classification	Molecular pattern	Note
HFE-related	p.Cys282Tyr homozygosity or compound heterozygosity of p.Cys282Tyr with other rare HFE pathogenic variants106, 107, 108, 109 or HFE deletion110	Low penetrance; consider presence of host-related or environmental cofactors for IO In subjects with other HFE genotypes (eg, 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 (GOF)-related	Potentially, mutations 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 centers, but the diagnosis of non-HFE related HC is sufficient to start phlebotomies at nonspecialized centers*
Digenic†	Double heterozygosity and/or double homozygosity/heterozygosity for mutations in 2 different genes involved in iron metabolism (HFE and/or non-HFE)	More commonly, p.Cys282Tyr mutation in HFE gene might coexist with mutation in other genes; rarely, both mutations 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

^*Provided that IO is confirmed by MRI. If this is not accessible, close monitoring of Hb level is needed to avoid the occurrence of anemia.

^†Caution is needed to interpret as digenic inheritance results from NGS 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.