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HFE and hemochromatosis: time to reconsider the diagnostic role of the p.His63Asp variant

Year: 2025

Type: article

Abstract: Hemochromatosis, primarily caused by homozygosity for the HFE p.Cys282Tyr variant, is the most frequent genetic iron overload disorder in populations of Northern European ancestry. Since the discovery of the HFE gene, genetic testing for HFE-related hemochromatosis has frequently included both the p.Cys282Tyr and the more common p.His63Asp variant. However, growing evidence indicates that the p.His63Asp variant lacks clear pathogenic significance in most clinical contexts related to iron overload, and its routine reporting may lead to diagnostic confusion and inappropriate management. This manuscript calls for a clarification of current genetic testing practices in hemochromatosis, recommending that testing for HFE -related hemochromatosis be restricted to the p.Cys282Tyr variant. This position is grounded in current scientific evidence and aims to improve diagnostic accuracy, reduce patient harm, and promote more consistent clinical interpretation.

Source: Blood Red Cells & Iron

DOI: 10.1016/j.brci.2025.100034

Authors: Jeremy Shearman, John K. Olynyk, Sonia Distante, Graça Porto, Mayka Sanchez