Albertine Donker

Chapter 4 156 Overall, i) patients with bi-allelic, severe gene defects had the most severe phenotype, but exceptions occurred, and genotype alone was not fully predictive for the response to oral iron, ii) mono-allelic patients presented later in life with anemia (median 31 years, range 10 – 47 years) than bi-allelic patients (median 4.5 years, 0-33 years, Mann-Whitney p=0.03), were more likely to be females and had a milder phenotype with respect to severity of anemia, microcytosis and duration of intravenous iron treatment. Since patients with identical defects were scarce, our patient series do not allow to decipher a clear influence of the presence of the high frequency TMPRSS6 variant c.2207C>T (p.Ala736Val) on the severity of the disease ( Supplemental Table 6 ). Nevertheless, our data suggest that for prediction of the phenotype, the nature of the pathogenic TMPRSS6 defect overrides a possible influence of the c.2207C>T (p.Ala736Val) variant. Interestingly, mono-allelic mutated relatives with the same TMPRSS6 defect as the probands, screened at the time of diagnosis of the proband, were not affected at all, except for the mother of patient 17. In two sibling pairs with identical heterozygous TMPRSS6 variants but different phenotypes parental haplotype analysis was performed ( Supplemental Table 8 ). In the family of patient 19, both the female proband and her unaffected sister inherited the mutant allele from their mother. However, they received different paternal alleles. Their unaffected brother received two wild type alleles from his mother and father. In the family of patient 20, genetic data were only available from the proband and her sister, not from the parents. Both the female proband and her unaffected sister shared the same TMPRSS6 variant, but had different wild type alleles, indicating different parental haplotypes of the ‘healthy’ allele. Although based on analysis of only two families these data suggest that in individuals with a heterozygous TMPRSS6 variant, differences in their 2 nd allele that is designated as ‘wild type’ account for difference in IRIDA phenotype. TSAT/hepcidin ratio in IRIDA patients and their unaffected relatives We evaluated TSAT/hepcidin ratios in i) bi-allelic probands ii) mono-allelic probands, iii) bi-allelic relatives, iv) mono-allelic relatives and iv) wild-type relatives for whom the TSAT and hepcidin were determined and who had no signs of inflammation.