Suzanne de Bruijn

30 Chapter 1.1 whole exome sequencing (WES) and homozygosity mapping. RNA expression analyses and immunohistochemistry were performed to provide additional evidence for the pathogenicity of KIAA1549 variants. Chapter 3 focuses on the identification of the genetic defect and the development of a genetic therapy for adult-onset HL type DFNA21. The identification of the genetic defect using WES is described in chapter 3.1. The defect is an in-frame deletion in the RIPOR2 gene and is positioned 0.9 Mb centromeric of the DFNA21 locus, a locus that was identified using linkage analysis over twenty years ago. The RIPOR2 variant is associated with adult-onset dominantly HL, and presumably the most frequent cause of this type of HL in Northwest Europe. Because of this high prevalence, the first steps towards the development of an allele-specific therapy for RIPOR2 -associated HL were initiated, which is described in chapter 3.2 . One of the limitations of WES as compared to whole genome sequencing (WGS) is the detection of structural variants (SV). In chapter 4 , we describe the successful application of WGS leading to the identification of eight unique SVs in 22 families affected with autosomal dominant RP. These SVs show overlap with the previously described genetically unresolved RP17 locus. Epigenetic and chromatin analyses were performed to elucidate a novel mechanism of disease: the ectopic expression of the GDPD1 gene. In chapter 5 , a phenotype-genotype correlation study was performed to explain the relatively high missing heritability for SLC26A4 -associated HL. Sequencing technologies that were performed include both short and long-read WGS. Important clues for the missing heritability were identified, including a commonly shared disease haplotype and indications for possible digenic inheritance. Finally, chapter 6 provides the general discussion and, future perspectives whereas chapter 7 provides the summary of this thesis.