@article {de Bruijnjmedgenet-2020-106863, author = {Suzanne E de Bruijn and Jeroen J Smits and Chang Liu and Cornelis P Lanting and Andy J Beynon and Jo{\"e}lle Blankevoort and Jaap Oostrik and Wouter Koole and Erik de Vrieze and Cor W R J Cremers and Frans P M Cremers and Susanne Roosing and Helger G Yntema and Henricus P M Kunst and Bo Zhao and Ronald J E Pennings and Hannie Kremer}, editor = {, and , and van Dooren, M F and de Gier, H H W and Hoefsloot, E H and van der Schroeff, M P and Kant, S G and Rotteveel, L J C and Ropers, F G and Widdershoven, J C C and Hof, J R and Vanhoutte, E K and Admiraal, R J C and Feenstra, I and Kremer, H and Lanting, C P and Pennings, R J E and Yntema, H G and Free, R H and Klein Wassink-Ruiter, J S and Stokroos, R J and Smit, A L and van den Boogaard, M J and Ebbens, F A and Maas, S M and Plomp, A and Goderie, T P M and Merkus, P and van de Kamp, J M}, title = {A RIPOR2 in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss}, elocation-id = {jmedgenet-2020-106863}, year = {2020}, doi = {10.1136/jmedgenet-2020-106863}, publisher = {BMJ Publishing Group Ltd}, abstract = {Background Hearing loss is one of the most prevalent disabilities worldwide, and has a significant impact on quality of life. The adult-onset type of the condition is highly heritable but the genetic causes are largely unknown, which is in contrast to childhood-onset hearing loss.Methods Family and cohort studies included exome sequencing and characterisation of the hearing phenotype. Ex vivo protein expression addressed the functional effect of a DNA variant.Results An in-frame deletion of 12 nucleotides in RIPOR2 was identified as a highly penetrant cause of adult-onset progressive hearing loss that segregated as an autosomal dominant trait in 12 families from the Netherlands. Hearing loss associated with the deletion in 63 subjects displayed variable audiometric characteristics and an average (SD) age of onset of 30.6 (14.9) years (range 0{\textendash}70 years). A functional effect of the RIPOR2 variant was demonstrated by aberrant localisation of the mutant RIPOR2 in the stereocilia of cochlear hair cells and failure to rescue morphological defects in RIPOR2-deficient hair cells, in contrast to the wild-type protein. Strikingly, the RIPOR2 variant is present in 18 of 22 952 individuals not selected for hearing loss in the Southeast Netherlands.Conclusion Collectively, the presented data demonstrate that an inherited form of adult-onset hearing loss is relatively common, with potentially thousands of individuals at risk in the Netherlands and beyond, which makes it an attractive target for developing a (genetic) therapy.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/early/2020/05/13/jmedgenet-2020-106863}, eprint = {https://jmg.bmj.com/content/early/2020/05/13/jmedgenet-2020-106863.full.pdf}, journal = {Journal of Medical Genetics} }