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Original research
A RIPOR2 in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss
  1. Suzanne E de Bruijn1,2,
  2. Jeroen J Smits2,3,
  3. Chang Liu4,
  4. Cornelis P Lanting3,
  5. Andy J Beynon3,
  6. Joëlle Blankevoort1,
  7. Jaap Oostrik2,3,
  8. Wouter Koole1,
  9. Erik de Vrieze2,3,
  10. Cor W R J Cremers3,
  11. Frans P M Cremers1,2,
  12. Susanne Roosing1,2,
  13. Helger G Yntema1,2,
  14. Henricus P M Kunst3,5,
  15. Bo Zhao4,
  16. Ronald J E Pennings2,3,
  17. Hannie Kremer1,2,3
  18. DOOFNL Consortium
    1. 1 Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands
    2. 2 Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands
    3. 3 Department of Otorhinolaryngology, Radboudumc, Nijmegen, The Netherlands
    4. 4 Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
    5. 5 Radboud Institute for Health Sciences, Radboudumc, Nijmegen, The Netherlands
    1. Correspondence to Professor Hannie Kremer, Department of Otorhinolaryngology and Human Genetics, Radboudumc, Nijmegen 6500 HB, Netherlands; Hannie.Kremer{at}


    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 0–70 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.

    • genetics
    • molecular genetics
    • human genetics

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    • Twitter @SEdeBruijn, @suussuus84

    • SEdB and JJS contributed equally.

    • RJEP and HK contributed equally.

    • Collaborators The DOOFNL consortium is a Dutch nationwide collaboration on hereditary hearing loss and consists of MF van Dooren, HHW de Gier, EH Hoefsloot, MP van der Schroeff (ErasmusMC, Rotterdam, the Netherlands), SG Kant, LJC Rotteveel, FG Ropers (LUMC, Leiden, the Netherlands), JCC Widdershoven, JR Hof, EK Vanhoutte (MUMC+, Maastricht, the Netherlands), RJC Admiraal, I Feenstra, H Kremer, CP Lanting, RJE Pennings, HG Yntema (Radboudumc, Nijmegen, the Netherlands), RH Free and JS Klein Wassink-Ruiter (UMCG, Groningen, the Netherlands), RJ Stokroos, AL Smit, MJ van den Boogaard (UMC, Utrecht, the Netherlands) and FA Ebbens, SM Maas, A Plomp, TPM Goderie, P Merkus and J van de Kamp (Amsterdam UMC, Amsterdam, the Netherlands). Specifically for this study, DOOFNL members RJCA, SGK, LJCR, SMM and JvdK contributed subjects with the RIPOR2 variant. Other members of the consortium contributed subjects to the cohort of index cases.

    • Contributors SEdB and JJS co-designed the study, conducted experiments, analysed the data, wrote the manuscript and JJS performed subject evaluation. CL performed the experiments in mouse cochlear explants and Co-IP experiments and revised the manuscript. CPL and AJB analysed the audiovestibular data and revised the manuscript. EdV discussed experimental design and critically read the manuscript. JB and JO conducted and analysed the genetic analyses. WK and HGY analysed the WES data and revised the manuscript. FPMC and SR discussed the experimental design and critically read the manuscript. HPMK performed clinical evaluations for members of family W97-056. BZ co-designed and supervised the studies in mouse cochlea and the Co-IP experiments, and revised the manuscript. RJEP clinically evaluated family members, RJEP and HK co-designed the study, supervised the project and revised the manuscript. All authors read and approved the final manuscript.

    • Funding This study was financially supported by a DCMN Radboudumc grant, by a grant of the Heinsius-Houbolt foundation and an NIH/NIDCD (R01 DC017147) grant.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Data not included in the manuscript or supplementary data file are available upon reasonable request (