Submission Details

HFE, also known as HLA-H, was first reported in relation to autosomal recessive hemochromatosis type 1 in 1996 (Feder et al., PMID:8696333). Hemochromatosis type 1 is characterized by defective regulation of dietary iron absorption resulting in excessive iron accumulation in the body. The disease presents biochemically as elevated serum transferrin-iron saturation and serum ferritin. Patients can be diagnosed and treated for the disease based on the biochemical profile before the onset of clinical manifestations. Clinical manifestations include cirrhosis, liver fibrosis, diabetes mellitus and restrictive cardiomyopathy. At least nine variants, all missense except for one nonsense, have been reported in humans. Two common variants of low penetrance are specifically associated with this disease: C282Y and H63D. It is estimated that 80% or more hemochromatosis type 1 cases carry the C282Y variant. Evidence supporting this gene-disease relationship includes case-level data, case-control data, segregation data, and experimental data.

This gene-disease relationship is supported by animal models, expression studies, and in vivo functional assays (PMIDs:1467310, 9482913, 25970244, 9122230, 10756356). RNA sequencing and patient tissue staining both show expression of HFE in the liver, small intestine and spleen which are all relevant tissues to the disease (PMIDs:25970244, 9122230). Immunocytochemistry of C282Y/C282Y patient cells also shows that the expression of *HFE *on the cell surface of leukocytes is decreased as compared to wildtype (PMID:10756356). A knockout mouse recapitulates the human phenotype: abnormally high transferrin saturation and excessive iron accumulation in the liver (PMID:9482913). A knockin of the C282Y/H63D and H63D/H63D genotypes also demonstrated results consistent with the biochemical and histopathological results seen in humans with the same genotype (PMID:14673107). More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached.

Variants in this gene have been reported in hundreds of probands in more than 20 publications (PMIDs:16979952, 18762941, 39568488, 10575540, 38560130, 40034140, 11565552, 11336458, 18809761, 15366698, 37069863, 32153640, 30339210, 9687253, 8696333). Variants in this gene segregated with disease in over 100 additional family members. This gene-disease relationship has been studied in at least one case-control study (PMID:8696333) at the aggregate variant level. All of Us also reports on the association of HFE genotypes with hemochromatosis phenotypes (PMID:40034140). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached.

In summary, there is definitive evidence to support the relationship between HFE and autosomal recessive hemochromatosis type 1. This evidence has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on the meeting date June 27, 2025 (SOP Version 11).