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Iron Stories

“Iron Genes” and Where (and How) to Find Them

V. Nathan Subramaniam
Hepatogenomics Research Group, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
The identification of variants in subjects with clinical iron disease has been invaluable in the pursuit of genes involved in iron metabolism and provided new mechanistic insights into how iron is regulated (1, 2, 3). This is particularly relevant to the identification of the group of genes collectively termed non-HFE which are associated with rare iron overload disorders not linked to the more common mutations in the HFE gene (homeostatic iron regulator). Of particular significance to the identification of new genes are the various private and public databases and patient registries with carefully collected clinical data and biological samples. This collaborative research between clinicians and researchers is at the forefront of new developments in the iron field. With the advent of new technologies (e.g., next-generation sequencing (NGS) and spatial transcriptomics) these precious biological and clinical resources provide the basis for new discoveries and in the determination of the prevalence of disease (6).
Viveiros et al (7) reported a recent innovative approach in using advanced non-invasive imaging, clinical biochemistry and NGS in the iron field, to guide the identification of the potential genetic basis of iron overload disease. In this approach body iron levels were quantified by non-invasive means, and this then used to guide the next-generation sequencing of patients with increased iron levels (4. 5). In this study HFE genotyping of a cohort of patients with high serum ferritin levels [greater than 200 ug/L (women) and 300 ug/L (men)] was performed. Magnetic Resonance Imaging (MRI) was used to quantify hepatic and splenic iron levels. 10% of the patients were found to be homozygous for p.C282Y variants in HFE. Patients without the HFE p.C282Y variant were stratified by hepatic iron accumulation. Next-generation sequencing performed on 180 patients identified variants in a number of iron-related genes: Bone Morphogenetic Protein 6, Ceruloplasmin, Hepcidin, Ferroportin and Transferrin receptor 2. This study suggested that the probability of identifying pathogenic genetic variants by NGS could be improved by preselecting those with low splenic iron levels, and that high hepatic and low splenic iron levels predicted the identification of variants in hemochromatosis genes.
  1. Camaschella C, Fargion S, Sampietro M, Roetto A, Bosio S, Garozzo G, Arosio C, Piperno A. Inherited HFE-unrelated hemochromatosis in Italian families. Hepatology. 1999;29:1563-4.
  2. Wallace DF, Subramaniam VN. Non-HFE haemochromatosis. World J Gastroenterol. 2007;13:4690-8.
  3. Pietrangelo A, Caleffi A, Corradini E. Non-HFE hepatic iron overload. Semin Liver Dis. 2011;31:302-18.
  4. Badar S, Busti F, Ferrarini A, Xumerle L, Bozzini P, Capelli P, Pozzi-Mucelli R, Campostrini N, De Matteis G, Marin Vargas S, Giorgetti A, Delledonne M, Olivieri O, Girelli D. Identification of novel mutations in hemochromatosis genes by targeted next generation sequencing in Italian patients with unexplained iron overload. Am J Hematol. 2016;91:420-5.
  5. McDonald CJ, Ostini L, Wallace DF, Lyons A, Crawford DH, Subramaniam VN. Next-generation sequencing: Application of a novel platform to analyze atypical iron disorders. J Hepatol. 2015;63:1288-93.
  6. Wallace DF, Subramaniam VN. The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data. Genet Med. 2016;18:618-26.
  7. Viveiros A, Schaefer B, Panzer M, Henninger B, Plaikner M, Kremser C, Franke A, Franzenburg S, Hoeppner MP, Stauder R, Janecke A, Tilg H, Zoller H. MRI-Based Iron Phenotyping and Patient Selection for Next-Generation Sequencing of Non-Homeostatic Iron Regulator Hemochromatosis Genes. Hepatology. 2021;74:2424-35.

posted: May 27, 2022