Albertine Donker

IRIDA: a Heterogeneous Disease 145 4 RESULTS Patient characteristics We report 21 IRIDA patients from 20 unrelated families. IRIDA was diagnosed in case of the combination of a relevant phenotype and genotype. After exclusion of other conditions as the (exclusive) explanation, a patient with a current or past microcytic hypochromic anemia, in absence of inflammation, not or partially responsive to oral iron with a low TSAT (< 10 %) was considered as a suspected case, after which serum hepcidin analysis was performed in 20 out of 22 patients and genotyping of TMPRSS6 in all patients. In our diagnostic work-up, very low to elevated ferritin levels, either before or after treatment with iron supplementation could fit the diagnosis. Nine female and five male patients were diagnosed with a bi-allelic TMPRSS6 defect ( Table 1 A ). In patient 1, comparative genomic hybridization was performed since no signal of TMPRSS6 was obtained by Sanger sequencing. A homozygous deletion of 118 kb was detected in 22q12.3, with the distal breaking point in intron 2 of the TMPRSS6 gene (deletion breakpoints at Mb positions 37,374,751 and 37,492,851), effectively knocking out exons 3 – 18 (UCSC Genome Browser on Human Feb 2009 GRCh 37/hg 19 assembly; 26 Supplemental Figure 1 ). (In the other seven patients (all female) only a mono-allelic TMPRSS6 defect was found ( Table 1 B ). In these patients MLPA showed no large deletions and/or duplications in the 2 nd allele. For the bi-allelic affected patients, age at the time of evaluation for IRIDA ranged from 1 to 40 years; 10 out of 14 patients were in their first or second decade. Evaluation for IRIDA of the 7 heterozygous patients all occurred in the third or fourth decade.