Suzanne de Bruijn

29 General introduction and plotted in a decade audiogram, illustrating hearing threshold development over time. This could serve as a phenotype fingerprint, especially for specific HL types with a high phenotype-genotype correlation. 48 Additionally, machine-learning efforts have been performed, in order to develop an algorithm that is able to predict the underlying cause based on an individual’s audiogram. Using the machine-learning tool Audiogene, accuracies of up to 68% can be reached for dominantly inherited HL, which indicates there is still room for improvement. 49 Considering the extremely high genetic but also clinical heterogeneity of HL, the identification of a causative variant is still a complicated task. The different aspects of disease variant identification and interpretation will be discussed in more detail in chapter 1.2. Despite all technological advancements and insights that are gained during thirty years of research directed towards the identification of disease-associated genes and variant interpretation, still a significant number of cases remain genetically unexplained for both inherited HL and RD. With this, it is clear that still many challenges are ahead of us that need to be overcome in the following years to finally be able to completely “ solve the unsolved” . OUTLINE AND AIMS OF THIS THESIS Inherited RD and HL are both characterized by a large clinical and genetic heterogeneity. Despite the large number of genes that have been associatedwith these disorders (>270 and >150, respectively), literature reports still indicate a significant missing heritability. The research described in this thesis aimed to shed light on this missing heritability, and to solve the unsolved cases by combining established methods, implementing novel approaches and sometimes by thinking “outside the box”. This has led to several important findings and relevant contributions to the field that are described in the different chapters of this thesis. Chapter 1.2 provides a comprehensive overview of available technologies that contributed over the years to the identification of RD and HL-associated genes and can be applied in modern diagnostics. Additionally, the step-wise approach of disease variant identification and interpretation is described, with a special focus on inherited RD and HL. Chapter 2 describes the confirmation of a candidate gene for RD. Pathogenic variants in the KIAA1549 gene have been detected using a combined approach involving both