Suzanne de Bruijn

101 A RIPOR2 deletion is a frequent cause of adult-onset hearing loss INTRODUCTION Hearing loss (HL) is one of the most prevalent disabilities worldwide 1 and genetic factors importantly contribute to this condition. So far, 118 genes have been associated with nonsyndromic forms of sensorineural HL and variants in these genes explain a significant part of subjects with an early onset of HL, i.e., congenital or in childhood. 2-4 Our knowledge of the genetic architecture of adult-onset HL is limited despite a high heritability which is estimated to be 30-70%. 5-7 Differences in phenotypic parameters that are used and age ranges of study participants may well contribute to the variation in the reported heritability. As summarized by Lewis et al. 8 , genome-wide association studies (GWAS) of hearing status in adults and genetic analyses of families with dominantly inherited post-lingual onset HL indicate that both common variants and rare variants contribute to adult-onset HL with a small and large effect size, respectively. Such variants may or may not affect genes that are already known to function in the auditory pathway. Previously, we identified a 12.4-Mb locus for adult-onset HL on chromosome 6 (p24.1- 22.3): DFNA21. 9,10 However, the underlying pathogenic variant in the studied family (W97-056) remained elusive. Here, we present the identification of an in-frame deletion (c.1696_1707del; NM_014722.3) in RIPOR2 (RHO Family Interacting Cell Polarization Regulator 2) to underlie autosomal dominant nonsyndromic HL (adNSHL) in this family and in 11 additional (large) families of Dutch origin. The allele frequency (AF) of this variant suggests that it potentially explains adult-onset HL in thousands of individuals in the Netherlands and Northwest Europe. Our study expands the phenotypic spectrum associated with RIPOR2 defects which had so far only been described to underlie early- onset recessively inherited HL. 11 MATERIALS AND METHODS Study approval The study of human subjects was approved by the medical ethics committee of the Radboudumc (registration number: NL33648.091.10) and performed in accordance with the principles of the World Medical Association Declaration of Helsinki. Written informed consent was obtained from all participants or their legal representatives. All animal experiments were approved by the Institutional Animal Care and Use Committee of Indiana University School of Medicine (registration number 19075).