Suzanne de Bruijn

284 Chapter 6 Not all cases included in this thesis could be (completely) resolved. Chapter 5 described the investigation of a Dutch cohort of individuals affected by HL and monoallelic pathogenic SLC26A4 variants. In the majority of the monoallelic cases, a common shared haplotype (previously coined as the “CEVA” haplotype) was detected. Despite the characterization and detailed interrogation of the haplotype using both short-read and long-read sequencing as well as optical genome mapping, no putative causative defect was found that could be associated with HL. This indicates that despite all the advancements, the understanding of the human genome is still incomplete. In the current chapter, the importance of genetic diagnostics, its limitations and the most important challenges are discussed. Special attention is paid to upcoming developments that are necessary to address these challenges in the years to come. Some might believe that closing the diagnostic gap will soon become within reach. Nevertheless, several hurdles have to be overcome first. THE IMPORTANCE OF GENETIC DIAGNOSTICS Why do we strive to provide a genetic explanation for all individuals affected with a disorder that is thought to have a genetic cause? In most cases, receiving a genetic diagnosis has a significant impact on a patient’s life. Clinical care and counseling can be optimally fitted to the patient’s needs, possibilities regarding family planning can be discussed, and in some cases, therapeutic options become available. Patient counseling A conclusive genetic diagnosis is crucial for a clinician to be able to provide a patient with optimal care and counseling. Based on the genetic diagnosis, different questions may arise related to disease progression, genetic risks of family members and the risk to develop a syndromic phenotype. Special attention can be paid to fitted rehabilitation options, such as hearing aids for individuals affected by HL or light-filtering glasses for RD. In case of an (anticipated) syndromic phenotype, additionally, pre-symptomatic care can be initiated (e.g. thyroid evaluation in individuals affected with HL and pathogenic SLC26A4 variants ( chapter 5 )). A genetic diagnosis can help individuals to set their personal expectations and can be experienced as an important relief. Studies have revealed that a genetic diagnosis can have significant emotional consequences and that special attention should be paid to psychological well-being. 10 Unfortunately, not every genetic diagnosis will provide conclusive answers to all questions. Variants in numerous HL- or RD-associated genes