Suzanne de Bruijn

319 Summary ENGLISH SUMMARY The inherited sensory disorders retinal dystrophies (RD) and hearing loss (HL) display an enormous degree of clinical and genetic heterogeneity. The clinical heterogeneity is characterized by the variability in age of onset, disease symptoms and disease progression, whereas the genetic heterogeneity is demonstrated by the large number of disease-associated genes (i.e. >270 RD-associated genes, >150 HL-associated genes). Despite this large number of genes, still many affected individuals lack a genetic diagnosis as no pathogenic variant (for autosomal dominant diseases), or not both pathogenic variants (for autosomal recessive diseases), could be identified using existing methodologies. A genetic diagnosis is essential for prognosis, counseling and eligibility for novel (genetic) therapies, and therefore it is of utmost importance to accommodate a genetic explanation for all affected individuals. With this in mind, the aim of this thesis was to shed light on the missing heritability involved in both inherited RD and HL. To increase the genetic diagnostic yield for these disorders, a combination of various techniques and approaches was applied. Chapter 1 provided a general background of inherited sensory disorders and genetic diagnostics. Chapter 1.1 addressed the anatomy of the eye and the inner ear, and the physiological processes involved that play a role in both health and disease. Special attention was paid to the different (genetic) causes that can underlie visual or hearing disorders. Chapter1.2 reviewed theavailableapproaches for diseasegene identification, and the subsequent improvements and refinements that have been introduced in the past decades. The advantages and limitations of different (sequencing) techniques and approaches were discussed, including their impact on genetic diagnostics. In the final part of this chapter, the importance and complexity of variant interpretation processes were discussed. Chapter 2 described the identification of pathogenic KIAA1549 variants using whole exome sequencing (WES). KIAA1549 was previously suggested to be a candidate gene associated with autosomal recessive retinitis pigmentosa (RP), however additional evidence was lacking. In this chapter, novel pathogenic KIAA1549 variants were described which strengthened the evidence for association of KIAA1549 with RP. RNA analyses confirmed expression of KIAA1549 in the human retina, and a retina-specific transcript was identified. Additionally, immunohistochemistry performed on murine retina sections revealed the presence of KIAA1549 in the photoreceptor connecting cilium and the outer plexiform layer. Altogether, there now is very strong evidence that KIAA1549 variants can underlie RP.