Submission Details

The HAMP gene encodes hepcidin, a human antimicrobial peptide that is predominantly expressed in the liver. Hepcidin functions as a key iron-regulatory hormone, playing a central role in systemic iron homeostasis (PMIDs: 11034317, 11113131, 11113132). In 2003, HAMP was first implicated in autosomal recessive hemochromatosis type 2B (HH2B) (Roetto et al., PMID: 12469120). HH2B is characterized by elevated transferrin saturation, serum ferritin and iron levels, increased liver transaminases, and hepatic iron accumulation. Clinical manifestations include cirrhosis, liver fibrosis, hepatosplenomegaly, cardiomyopathy, hyperpigmentation, hypogonadism, diabetes, arthritis, and hematological abnormalities. A range of pathogenic variants in HAMP has been reported in affected individuals, including missense, nonsense, and frameshift mutations, as well as a recurrent 5′UTR base change. This curation includes 12 unrelated probands and 9 unique variants (PMIDs: 12469120, 14630809, 15024747, 15099344, 15198949, 16960153, 19342478, 22297252, 29085829, 33016646, 36925058). The gene-disease relationship is strongly supported by case-level evidence, exceeding the maximum score of 12 points. Additional support comes from animal models, expression, and functional studies (PMIDs: 11034317, 11113131, 11113132, 16574947, 24816174, 15933050, 27897970, 12704388). Northern blot and RT-PCR analyses of human tissues confirmed that hepcidin is predominantly expressed in the liver (PMIDs: 11034317, 11113132). Studies in mice demonstrated that hepcidin expression is upregulated in response to increased serum and hepatic iron levels. Hepcidin regulates systemic iron concentration via the hepcidin–ferroportin axis, underscoring its central role in iron homeostasis (PMIDs: 11113132, 15933050). HAMP knockout (KO) mouse models recapitulate key features of the human HH2B phenotype, including elevated hepatic iron, serum iron, and ferritin levels (PMIDs: 16574947, 24816174). KO mice fed an iron-rich diet developed elevated liver enzymes, hepatomegaly, chronic liver inflammation, liver cell apoptosis, and tissue fibrosis, suggesting that hepcidin deficiency combined with iron overload contributes to liver injury (PMID: 24816174). Furthermore, transgenic overexpression of hepcidin in HFE KO mice rescued hepatic iron accumulation, reinforcing hepcidin’s role in iron regulation (PMID: 12704388). Cardiac-specific deletion of hepcidin led to heart enlargement, increased expression of hypertrophic markers MYH7 and NPPB, and cardiomyocyte apoptosis. These KO mice exhibited reduced cardiac function and impaired activity of iron-dependent and mitochondrial enzymes, which were restored upon iron supplementation. Additionally, ferroportin expression was upregulated in KO heart tissue, consistent with the loss of hepcidin-mediated regulation. This local iron deficiency, driven by enhanced iron efflux, was reversed by treating cultured cardiomyocytes with hepcidin (PMID: 27897970). In summary, there is definitive evidence supporting the association between HAMP and autosomal recessive hemochromatosis type 2B. This relationship has been consistently demonstrated in both research and clinical diagnostic settings and has remained robust over time. This classification was approved by the ClinGen IEM GCEP at the meeting on October 10, 2025 (SOP Version 11).