Browsing by Author "DOOFNL Consortium"

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    A RIPOR2 in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss
    (BMJ, 2020) de Bruijn, Suzanne E.; Smits, Jeroen J.; Liu, Chang; Lanting, Cornelis P.; Beynon, Andy J.; Blankevoort, Joëlle; Oostrik, Jaap; Koole, Wouter; de Vrieze, Erik; Cremers, Cor W.R.J.; Cremers, Frans P.M.; Roosing, Susanne; Yntema, Helger G.; Kunst, Henricus P.M.; Zhao, Bo; Pennings, Ronald J.E.; Kremer, Hannie; DOOFNL Consortium; Otolaryngology -- Head and Neck Surgery, School of Medicine
    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.
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    The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis
    (Springer, 2024) Colbert, Brett M.; Lanting, Cris; Smeal, Molly; Blanton, Susan; Dykxhoorn, Derek M.; Tang, Pei-Ciao; Getchell, Richard L.; Velde, Hedwig; Fehrmann, Mirthe; Thorpe, Ryan; Chapagain, Prem; Elkhaligy, Heidy; Kremer, Hannie; Yntema, Helger; Haer-Wigman, Lonneke; Redfield, Shelby; Sun, Tieqi; Bruijn, Saskia; Plomp, Astrid; Goderie, Thadé; van de Kamp, Jiddeke; Free, Rolien H.; Wassink-Ruiter, Jolien Klein; Widdershoven, Josine; Vanhoutte, Els; Rotteveel, Liselotte; Kriek, Marjolein; van Dooren, Marieke; Hoefsloot, Lies; de Gier, Heriette H. W.; DOOFNL Consortium; Schaefer, Amanda; Kolbe, Diana; Azaiez, Hela; Rabie, Grace; Aburayyan, Armal; Kawas, Mariana; Kanaan, Moien; Holder, Jourdan; Usami, Shin-Ichi; Chen, Zhengyi; Dai, Pu; Holt, Jeffrey; Nelson, Rick; Choi, Byung Yoon; Shearer, Eliot; Smith, Richard J. H.; Pennings, Ronald; Liu, Xue Zhong; Otolaryngology -- Head and Neck Surgery, School of Medicine
    TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.