Suzanne de Bruijn

18 Chapter 1.1 trans-retinol, transported to the RPE where it will be converted to 11-cis-retinal and transported back to the outer segment discs. Correct functioning of the retinoid cycle is crucial for maintaining light sensitivity. 5 INHERITED RETINAL DYSTROPHIES Inherited retinal dystrophies (RDs) areagroupof clinicallyandgeneticallyheterogeneous disorders that mainly involve the dysfunction or death of the photoreceptor and RPE cells. 11 Collectively, it is estimated that inherited RDs affect at least 2 million people worldwide. 8 Clinically, RDs can be broadly subdivided in three categories based on the primarily affected cell type: (1) the rod photoreceptors (e.g. retinitis pigmentosa and choroideremia), (2) the cone photoreceptors (e.g. macular or central dystrophies) and (3) more generalized types of RDs that involve both photoreceptor types (e.g. cone- rod and rod-cone dystrophies and Leber congenital amaurosis). However in practice, this distinction is not always clear as RDs often display overlapping clinical features especially in later stages of disease. Additionally, RDs can be classified as stationary (e.g. congenital stationary night blindness and achromatopsia) or progressive (e.g. retinitis pigmentosa, cone-rod dystrophy, Stargardt disease). RD phenotypes can be involved in non-syndromic or syndromic forms of disease that affect multiple organs or tissues. Consequences of RDs are highly variable and range from mild retinal dysfunction to (congenital) legal blindness in the most severe cases. 11,12 Genetically, RDs are associated with pathogenic variants in more than 270 genes and can be inherited in an autosomal recessive, dominant, X-linked or digenic fashion. 13 The RD-associated genes encode proteins that are involved in a multitude of biochemical processes. A gene ontology (GO) term-enrichment analysis was performed to visualize the biochemical processes that are most significantly enriched for RD-associated proteins ( Figure 2 ). Most significantly enriched processes include sensory and visual perception of light stimuli and cilium assembly and organization. Once a new potentially pathogenic variant is identified in a gene that has not been previously associated with RD, the interpretation and implication of this finding can be challenging. Variants within the same gene can be associatedwith different phenotypes, and the same phenotype can be caused by variants in different genes. Additionally, the phenotype can be affected by genetic modifiers as well as environmental factors, which can give rise to inter- and intrafamilial variability. The large genetic heterogeneity of RDs and the complexity of subsequent genetic analyses will be discussed in more detail in chapter 1.2 of this thesis.