Suzanne de Bruijn

285 General discussion and perspectives (e.g. CDH23 11 , USH2A 12 ) are associated with highly variable phenotypes. Part of this variability can be attributed to the variant type or genomic position of the variant, but it cannot be explained in all cases. Even a single genetic variant can lead to a wide spectrum of phenotypic expression, as observed for the in-frame RIPOR2 deletion described in chapter 3.1 . Therefore, a clinician must always be cautious when providing counseling on prognosis. Family planning Depending on the genetic diagnosis, the severity of the disorder and the expected inheritance pattern, reproductive options can be discussed. For severe disorders that meet strict criteria that differ per country, a preimplantation genetic diagnosis (PGD) procedure canbe initiated for a couplewitha knownaffected status (dominant disorders) or when both parents are known carriers of disease-causing variants affecting the same gene (recessive disorders). PGD is a form of in vitro fertilization (IVF) performed in the laboratory to yield several embryos. These embryos are genetically tested to determine the genotype, and only embryos without the specific genetic defect(s) will be used for implantation. 13 Alternatively, if a couple wishes to conceive a child naturally, prenatal testing can be performed. There are several options available that allow screening of the genotype of the fetus. When it appears that the embryo carries a genetic defect, it can be decided to terminate the pregnancy. Invasive prenatal genetic tests (e.g. chorionic villus sampling) have been available for some decades now. More recently, also a non- invasive test has been implemented in clinical settings as well. 14 When performing non- invasive prenatal testing (NIPT), a blood sample is drawn from the pregnant mother, which contains cell-free fetal DNA from the placenta that is subjected to genetic testing. 15,16 To be eligible for PGD or prenatal testing, the genetic diagnosis has to leave no room for doubt. One cannot risk to erroneously select an embryo with a misinterpreted genetic status. For some years, KIAA1549 was only considered a candidate disease gene for RP. With the identification of additional RP cases affected by pathogenic KIAA1549 variants ( chapter 2 ), causality of these variants in RP is now considered conclusive and KIAA1549 is included in diagnostic gene panels for RD. Likewise, only after functional evidence was obtained that showed causality of RP17-associated structural variants (SVs) ( chapter 4 ), the first PGD request has been recently approved for a member of the Dutch index RP17 family. This is one of the striking examples within this thesis of how molecular genetic findings can be swiftly translated to the clinic and thereby can have a significant impact on an individual’s life.