Albertine Donker

IRIDA: a Heterogeneous Disease 153 4 Haplotype analysis exploiting 10 intragenic HFV’s with a Minor Allele Frequency in Caucasians of > 0.005 and three Short Tandem Repeats surrounding TMPRSS6 was performed in patients with identical defects. The results were consistent with a common ancestor of the Dutch patients 3 and 4, who all carried the c.497delT defect. For the other patients with this defect the haplotype analysis might indicate relationship but was less clear. The haplotype analysis of patients with the c.1904_1905dup defect, found in three patients (5, 6 and 12) from Turkish origin, was consistent with a common ancestor of the patients 5 and 6. Patients 8 and 13 who carried the c.12282T>C defect might be related but haplotype analysis was not clearly indicative. ( Supplemental Table 7 ). We conclude that i) in the Netherlands certain defects are more prevalent than others, ii) patients who share a country of origin are likely to share specific defects and iii) common ancestry of patients with identical defects is not always obvious. Genotype-phenotype relation The IRIDA phenotype was highly variable in our population ( Table 1 ). To improve insight in genotype-phenotype relation we categorized the probands by six different groups based on the nature of the defect ( Table 1 ). Patients with large deletions either bi-allelic (ID 1) or in combination with a frameshift defect (ID 2) had the most severe IRIDA phenotype with respect to age of presentation, severity of anemia, microcytosis and duration of treatment with intravenous iron. However, patient 3 and 4, who shared the same homozygous frameshift defect, had very different phenotypes; patient 4 was only temporarily treated with intravenous iron as a child while patient 3 received intravenous iron till the age of 21 years. Only two of the 14 bi-allelic patients responded to oral iron supplementation, i.e. patient 7 and 11. Interestingly, these patients had severe genotypes. Patient 13 with two missense defects was responsive to a combination of oral iron with vitamin C. Seven patients were diagnosed with IRIDA due to a variety of heterozygous TMPRSS6 defects ( Table 1 B ). The large deletion in patient 15 resulted in a more severe genotype than the frameshift, aberrant splicing and missense defects in the other heterozygous patients.