Suzanne de Bruijn

114 Chapter 3.1 variants in the genes that encode proteins of the indicated complex of the stereocilia taper. As the taper region is thought to be essential for anchoring the mechanosensory stereocilia, noise exposure is an obvious candidate environmental modifying factor. Fourteen subjects with the RIPOR2 variant reported noise exposure. However, we could not correlate onset or strong progression of HL with a preceding significant noise exposure. Four subjects with HL who did not have the RIPOR2 variant, are considered to be phenocopies. In the light of the heterogeneity in the etiology of HL, the occurrence of phenocopies is not unexpected. For individuals III:14 and III:20 (W97-056) a possible explanation for their HL is a Ménière-like disease and heavy smoking (COPD Gold III), respectively. 45,46 Subject III:10 (W04-262) might have inherited a cause of HL associated with vestibular problems from her mother, who married into the family. HL in subject III:21 of family W97-056 remains unexplained. The c.1696_1707del RIPOR2 variant was only reported in non-Finnish Europeans, with the exception of a single individual of African origin (gnomAD v3 genomes). Assuming that the AF of 0.0392% determined in the SE-NL cohort is comparable throughout the Netherlands, the c.1696_1707del RIPOR2 variant is estimated to be present in more than 13,000 individuals who are therefore at risk to develop HL or have developed HL already due to this variant. About 30,000 additional individuals can be calculated to be at risk, based on the AF of 0.0096% of the variant in Northwest Europe (gnomAD v2.1.1) with ~156 million inhabitants (United Nations Population Division estimates, 2019). This large number of individuals at risk to develop HL due to the c.1696_1707del RIPOR2 variant illustrates the need to gain broader estimates of the penetrance of the variant which was ~90% at the age of 50 years in the studied families. However, this calculated penetrance cannot be excluded to be biased because these families were included based on index cases with HL. Further insight in the age-related penetrance of c.1696_1707del RIPOR2 will pave the way for the identification of modifying factors which may convey handles for prevention. In conclusion, we demonstrate that an adult-onset type of HL (DFNA21) is relatively common and associated with a “mild” variant in RIPOR2 . Potentially, thousands of individuals in the Netherlands and beyond are at risk to develop HL. More such variants might well wait to be“unmasked”as (population-specific) frequent and highly penetrant causes of adult-onset HL. Because of the large number of subjects estimated to be at risk for HL due to the c.1696_1707del RIPOR2 variant, it is an attractive target for the development of a genetic therapy. The great progress that is being made for this in hearing disorders is promising. 47