HAMP – Hemochromatosis Type 2

Clinical Validity

Juvenile hemochromatosis type 2 is an autosomal recessive iron overload syndrome caused by biallelic loss‐of‐function variants in the hepcidin gene, HAMP. Six unrelated probands across five families have been reported with homozygous or compound heterozygous HAMP mutations leading to early‐onset systemic iron accumulation, including a consanguineous family with pseudo-dominant inheritance (2 affected; [PMID:15099344]) and additional cases in Nature Genetics and Blood ([PMID:12469120], [PMID:12663437]) as well as a Brazilian patient ([PMID:29085829]). Functional studies, including Hamp-deficient mouse models that recapitulate the human phenotype, further support a definitive role for HAMP deficiency in type 2 hemochromatosis. Accordingly, the gene–disease association is classified as Strong.

Genetic Evidence

Hemochromatosis type 2 follows an autosomal recessive inheritance pattern. Segregation analysis in the initial consanguineous pedigree demonstrated co‐segregation of HAMP variants in father and daughter ([PMID:15099344]; 1 affected relative). In total, six probands carry biallelic HAMP mutations, with variant classes including missense substitutions disrupting conserved cysteines (e.g., c.233G>A (p.Cys78Tyr)) and premature termination codons (e.g., p.Arg56Ter, p.Arg59Ter) across multiple populations. No recurrent founder allele has been defined; all variants are rare and predicted to abolish hepcidin function. These data fulfill ClinGen genetic evidence criteria for a Strong tier.

Functional Evidence

Hepcidin is the key negative regulator of iron export via ferroportin. Loss‐of‐function HAMP alleles lead to inappropriately low hepcidin levels, driving unrestrained iron absorption. Animal models with Hamp knockout display severe iron overload analogous to human juvenile hemochromatosis ([PMID:12663437]). In vitro studies of cysteine‐to‐serine substitutions demonstrate impaired ferroportin binding and peptide stability, supporting a haploinsufficiency mechanism. Collectively, these data meet Moderate ClinGen functional criteria.

Conflicting Evidence

No studies have refuted the link between biallelic HAMP mutations and juvenile hemochromatosis type 2.

Integrated Conclusion

AR HAMP mutations result in hepcidin deficiency and early‐onset systemic iron overload with endocrinopathy, hepatic injury, and hyperpigmentation. Genetic testing of HAMP should be included in diagnostic panels for patients under 30 years with iron‐loading phenotypes negative for common HFE variants. Therapeutic phlebotomy and iron chelation demonstrate efficacy once a molecular diagnosis is established.

Key Take-home: HAMP molecular testing provides a definitive diagnosis of juvenile hemochromatosis type 2 and guides targeted iron depletion therapy.

References

• Clinical Genetics • 2004 • A homozygous HAMP mutation in a multiply consanguineous family with pseudo-dominant juvenile hemochromatosis. PMID:15099344
• Nature Genetics • 2003 • Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. PMID:12469120
• Blood • 2003 • Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. PMID:12663437
• World Journal of Clinical Cases • 2017 • Juvenile hemochromatosis: HAMP mutation and severe iron overload treated with phlebotomies and deferasirox. PMID:29085829

Evidence Based Scoring (AI generated)