Department of Hematology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GE Nijmegen, The Netherlands.
Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GE Nijmegen, The Netherlands.
Genes (Basel). 2022 Jul 23;13(8):1309. doi: 10.3390/genes13081309.
Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive inherited form of iron deficiency anemia characterized by discrepantly high hepcidin levels relative to body iron status. However, patients with monoallelic exonic variants have also been reported to express the IRIDA phenotype. The pathogenesis of an IRIDA phenotype in these patients is unknown and causes diagnostic uncertainty. Therefore, we retrospectively summarized the data of 16 patients (4 men, 12 women) who expressed the IRIDA phenotype in the presence of only a monoallelic variant. Eight unaffected relatives with identical exonic variants were used as controls. Haplotype analysis was performed to assess the (intra)genetic differences between patients and relatives. The expression and severity of the IRIDA phenotype were highly variable. Compared with their relatives, patients showed lower Hb, MCV, and TSAT/hepcidin ratios and inherited a different wild-type allele. We conclude that IRIDA in monoallelic -affected patients is a phenotypically and genotypically heterogeneous disease that is more common in female patients. We hypothesize that allelic imbalance, polygenetic inheritance, or modulating environmental factors and their complex interplay are possible causes. This explorative study is the first step toward improved insights into the pathophysiology and improved diagnostic accuracy for patients presenting with IRIDA and a monoallelic exonic variant.
铁难治性缺铁性贫血（IRIDA）是一种常染色体隐性遗传性缺铁性贫血，其特征是相对身体铁状态而言，铁调素水平显著升高。然而，已有报道称单等位基因外显子变异的患者也表现出 IRIDA 表型。这些患者中 IRIDA 表型的发病机制尚不清楚，导致诊断不确定。因此，我们回顾性总结了 16 名仅存在单等位基因变异的患者（4 名男性，12 名女性）表现出 IRIDA 表型的数据。8 名具有相同外显子变异的无影响亲属作为对照。进行单倍型分析以评估患者和亲属之间的（种内）遗传差异。IRIDA 表型的表达和严重程度高度可变。与亲属相比，患者的 Hb、MCV 和 TSAT/铁调素比值较低，且遗传了不同的野生型等位基因。我们得出结论，单等位基因受累患者的 IRIDA 是一种表型和基因型均存在异质性的疾病，在女性患者中更为常见。我们假设等位基因不平衡、多基因遗传或调节环境因素及其复杂相互作用可能是原因。这项探索性研究是深入了解具有 IRIDA 和单等位基因外显子变异的患者的病理生理学和提高诊断准确性的第一步。
