Albertine Donker

General Discussion 315 9 However, data obtained fromGWAS explain only a small fraction of the genetic risk for particular diseases. 68 Therefore, substantial challenges remain for researchers and clinicians that aim to unravel the architecture of susceptibility of complex diseases, such as the disorders addressed in this thesis, and to translate the information gathered into improvements in clinical guidelines. One of these challenges involves the identification of disease-modifying genetic variants that lie in the middle of the spectrum of at one side very rare DNA sequences directly causing disease with a Mendelian inheritance pattern (high penetrance), and on the opposite side common DNA variants that have very weak effects (low penetrance), which can be identified by GWAS. These variants with both an intermediate allele frequency and penetrance can neither be detected by linkage analysis because of the relatively low penetrance nor by association studies because of the relatively low allele frequency. 68,69 Such variants could be identified by sequencing of candidate genes by WES in patients that have been diagnosed with a specific genetic defect by classical Sanger sequencing. We would suggest such an approach in our patients with microcytic anemias due to inherited disorders of iron metabolism or heme synthesis, for example in the patients with a phenotype of IRIDA in whom only a heterozygous TMPRSS6 defect was found. We would prefer a targeted WES, filtering only the relevant candidate genes since a major concern of genome-wide DNA sequencing techniques is still the identification of secondary, actionable findings. Those unintended findings might reveal genetic information not pertaining to the patient’s presenting conditioning, possibly raising negative consequences such as stigmatization, financial burden, discrimination in insurance and employment. 70 This is particularly relevant and challenging in the case of children, since the parents have to serve as substitute decision makers, weighing the potential benefits against the potential undesirable above-mentioned consequences of the disclosure of secondary findings. 71