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The association between HPX and hemochromatosis type 1 is supported by limited evidence. In the sole case report from Acta haematologica (2012) (PMID:22584997), a 46‑year‑old African American man with mild iron overload was found to be heterozygous for a HPX missense change (R371W, rs75307540) during a multi‑gene exome screening. This finding was observed in the context of additional variants in other iron regulatory genes, and no independent segregation or replication data for HPX were provided, thereby restricting the strength of the clinical assertion to a limited level.
Genetic evidence for HPX in hemochromatosis type 1 is currently constrained to this isolated report (1 proband (PMID:22584997)), without any further HPX‑specific cases or recurrence studies. Moreover, no valid coding HGVS variant meeting the required criteria could be extracted from the available data for HPX, and thus no representative variant is included in this summary.
Functional studies addressing HPX have primarily focused on protein quantitative trait levels in other contexts, such as age‑related macular degeneration (PMID:37089696), and have not provided experimental support for a pathogenic role in iron overload. Consequently, the available functional evidence does not bolster the clinical association between HPX and hemochromatosis type 1.
There is no segregation evidence available as no additional affected relatives carrying the HPX variant were reported. The genetic and experimental findings, taken together, underscore the currently limited clinical utility of using HPX as a diagnostic marker for hemochromatosis type 1.
Further studies with focused HPX variant screening, segregation analyses, and functional assays relevant to iron homeostasis are required to strengthen the evidence for an association. At present, clinicians and commercial entities should interpret HPX findings with caution until more robust data are accrued.
Key Take‑home: While HPX is implicated incidentally in a case of hemochromatosis type 1, its diagnostic value remains limited due to the lack of independent replication and supporting functional evidence.
Gene–Disease AssociationLimitedThe association is based on a single case report involving 1 proband (PMID:22584997) with an incidental HPX R371W finding in a multi‑gene assessment, lacking segregation and independent replication. Genetic EvidenceLimitedOnly one case has identified a heterozygous HPX variant without additional HPX‑specific cases or recurrence, limiting the genetic evidence. Functional EvidenceLimitedNo functional studies directly supporting a role for HPX in hemochromatosis type 1 were presented; available assays focused on unrelated phenotypes. |