Suzanne de Bruijn

305 General discussion and perspectives the past, and pathogenic variants that used to be overlooked are now finally recognized as potentially pathogenic. Important examples are described in this thesis. Frequent causes of RD and HL that were previously missed or misinterpreted can now be readily detected with a targeted analysis strategy (RP17-SVs for dominant RP cases, an in-frame RIPOR2 deletion for dominant HL). A novel disease mechanism, involving the ectopic expression of a gene, was identified. With these findings, hundreds of individuals finally received a genetic diagnosis. Additionally, we have learned to think outside of the box, and to question the established paradigms on the heritability of RD and HL. The ultimate key to future success, is to acknowledge that we do not understand all the mysteries of the human genome yet. There is still enough to learn, and there are phenomena that cannot be explained yet. Revisiting the “junk DNA” to recognize that essential, functional elements are hidden in the non-codingworldwas a crucial first step. To be able to find a genetic explanation for all unsolved cases of inherited HL or RD in the years to come, we should continue this road trip and be ready for new adventures. We have to dive into the depths of the human genome and be open for alternative genetic explanations that can involve complex regulatory and non-Mendelian mechanisms. We have to broaden the genomic landscape .