Albertine Donker

IRIDA: a Heterogeneous Disease 159 4 DISCUSSION We describe a Dutch case series of 21 IRIDA patients and their relatives. We found that patients with bi-allelic severe genotype defects had more severe IRIDA phenotypes than patients with milder TMPRSS6 defects. This corresponds to scarce data in literature, 4,5 where a tendency to a more severe IRIDA phenotype has been described in patients with bi-allelic nonsense TMPRSS6 defects compared to patients with missense defects. However, our data show that exceptions occur. We observed that for as many as seven out of 21 of our patients only a heterozygous TMPRSS6 defect was found. MLPA showed no deletions or duplications in the ‘healthy’ allele. We appreciate that we did not exclude mutations and deletions in the promotor region, deep intronic inversions or balanced translocations of chromosome 22. However, our findings corroborate previous reports on mono- allelic patients that present with an IRIDA phenotype, which is generally mild (reviewed in 4 ). Interestingly, none of the relatives with a heterozygous TMPRSS6 defect - except for one - were affected. We hypothesize that differences in phenotype between probands and relatives with identical genotypes might be ascribed to a different expression of the wild type TMPRSS6 allele compared to the affected allele in patients and in unaffected individuals. 35 Indeed, Serre et a l describe an array-based analysis of 643 genes expressed in lymphoblastoid cell lines, which shows that for a large proportion (22%) of them, including TMPRSS6, the two alleles are differentially expressed. This imbalance in allelic expression can at least partially be explained by epigenetic mechanisms such as lyonization in females and imprinting. 36 This hypothesis is substantiated by the results of our parental haplotype analysis performed in two families suggesting that differences in phenotype between probands and unaffected siblings with the same heterozygous TMPRSS6 defect is attributable to differences in inherited parental wild type alleles. The finding that the TSAT/hepcidin ratio is lower for bi-allelically mutated probands, than for mono-allelically mutated probands, reflects that the degree of dysregulation of hepcidin production in IRIDA probands is a sliding scale that correlates with the severity of the genotype. These observations suggest that the mode of inheritance in IRIDA is complex. Overall, our small amount of data on the genotype-phenotype correlation in IRIDA patients and their relatives support the notion that phenotypical penetrance of TMPRSS6 defects is influenced by other (epi)genetic and environmental factors such as growth, co-morbidity as inflammation and blood loss, corroborating some previous observations in mice and man. 37