Investigation of HFE Mutations Associated with Hemochromatosis the Case of Ordu Province

Hemochromatosis-Related HFE Mutations in Ordu

Abstract

Objective: Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterised by increased intestinal iron absorption and progressive systemic iron overload. Although the C282Y variant is the predominant cause of HH in Northern European populations, the distribution of HFE variants varies geographically, and data from different regions of Türkiye remain limited. This study aimed to evaluate the molecular spectrum of HFE gene variants and their biochemical correlates in patients investigated for HH in Ordu province, located in the Black Sea region of Türkiye.
Methods: A retrospective analysis was conducted of 100 patients who underwent HFE gene sequencing between January 2024 and October 2025. Demographic characteristics, hemoglobin, serum ferritin, serum iron, transferrin saturation (TS), and HFE genotypes were obtained from medical records. PCR-based amplification followed by next-generation sequencing on the Illumina MiSeq platform was performed. Variants were classified using international databases, including ClinVar, Franklin, VarSome, HGMD Public®, gnomAD, and dbSNP. Comparisons between variant carriers and non-carriers were analysed using the Mann–Whitney U and chi-square tests.
Results: Among the 1000 patients (53 males, 47 females; mean age 47.2 ± 17.1 years), 64 (64.0%) exhibited a wild-type HFE genotype, while 36 (36.0%) carried at least one variant. The c.187C>G (H63D) variant was the most common, with 30 heterozygotes and 3 homozygotes, followed by one case each of C282Y homozygosity, c.76 + 2 dup heterozygosity, and H63D + c.76+2 dup compound heterozygosity. Ferritin, serum iron, and hemoglobin levels did not differ significantly between variant carriers and non-carriers (p = 0.869, 0.204, and 0.674, respectively). However, elevated TS (> 45%) was observed significantly more often in variant carriers than in wild-type individuals (41.7% vs. 20.3%, p = 0.040), indicating an approximately 2.8-fold higher likelihood of high TS among carriers. The proportion of participants with ferritin > 400 µg/L did not differ significantly between groups. The highest ferritin level (6104 µg/L) was observed in a heterozygous H63D female patient with severe anemia, while the highest TS (99%) was detected in a patient without any detectable variants.
Conclusion: In this Black Sea cohort, H63D was the predominant HFE variant, whereas C282Y was rare, consistent with regional genetic patterns in Türkiye. Although HFE variants were not associated with significant differences in ferritin, their strong association with elevated TS suggests a measurable impact on iron handling. These findings highlight the importance of TS in the diagnostic evaluation of HH in regions where C282Y-related HH is uncommon. Larger multicenter studies incorporating imaging-based iron quantification are needed to better define genotype–phenotype relationships in the Turkish population.