Albertine Donker

Chapter 9 308 to oral iron supplementation. 20 The clinical and biochemical characteristics of the children did not fit any previously described microcytic anemia known at that time. WES revealed compound heterozygous TMPRSS6 defects in both patients that previously were described as pathogenic, thereby elucidating the genetic basis of this unusual clinical presentation of TMPRSS6 defects. 20 It also further uncovers the pathophysiology of IRIDA, which is characterized by a distribution of the absorbed orally supplemented iron to the RES, resulting in relatively high ferritin levels for the amount of body iron. Furthermore, the unbiased analysis of coding exons by WES might reveal genotypic variability of disorders, meaning that defects in multiple genes lead to the same clinical phenotype and that defects in the same gene might result in a variation in clinical phenotype, or that a combination of defects in genes involved in iron metabolismmodulates the phenotype. Anecdotal data suggesting that co-inheritance of HFE and ALAS2 variants might worsen the iron loading in patients with XLSA are a good example of the latter, 21 as further corroborated by the clinical course of patient 2B ( Chapter 6 3 ) who was diagnosed with both a p.Arg452His ALAS2 defect and a homozygous p.Cys282Tyr HFE defect. He developed iron loading already in his teens, while in the majority of XLSA patients IO does not become evident until the third or fourth decade. Since the patients we studied were diagnosed by a clinical presentation, followed by classical Sanger sequencing of the candidate gene, we might have assessed selected subpopulations of patients with a certain phenotype of a microcytic genetic disorder of iron metabolism or heme synthesis, and we might have missed defects in other disease-causing or modulating genes that explain the phenotype of the patients.