The natural history and genotype–phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis
Year: 2024
Type: article
Study design: Observational Study
Abstract: 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.
Source: Human Genetics
Authors: Brett M. Colbert, Cris Lanting, Molly Smeal, Susan Blanton, Derek M. Dykxhoorn, Pei-Ciao Tang, Richard L. Getchell, Hedwig Velde, Mirthe Fehrmann, Ryan Thorpe, Prem Chapagain, Heidy Elkhaligy, Hannie Kremer, Helger Yntema, Lonneke Haer-Wigman, Shelby Redfield, Tieqi Sun, Saskia Bruijn, Astrid Plomp, Thadé Goderie, Jiddeke van de Kamp, Rolien H. Free, Jolien Klein Wassink-Ruiter, Josine Widdershoven, Els Vanhoutte, Liselotte Rotteveel, Marjolein Kriek, Marieke van Dooren, Lies Hoefsloot, Heriette H. W. de Gier, M. F. van Dooren, S. G. Kant, H. H. W. de Gier, E. H. Hoefsloot, M. P. van der Schroeff, L. J. C. Rotteveel, F. G. Ropers, M. Kriek, E. Aten, J. C. C. Widdershoven, J. R. Hof, K. Hellingman, V. Vernimmen, H. Kremer, R. J. E. Pennings, I. Feenstra, C. P. Lanting, H. G. Yntema, F. L. J. Cals, L. Haer-Wigman, R. H. Free, J. S. Klein Wassink-Ruiter, A. L. Smit, M. J. van den Boogaard, A. M. A. Lachmeier, J. J. Smits, F. A. Ebbens, S. M. Maas, A. Plomp, T. P. M. Goderie, P. Merkus, J. van de Kamp, Amanda Schaefer, Diana Kolbe, Hela Azaiez, Grace Rabie, Armal Aburayyan, Mariana Kawas, Moien Kanaan, Jourdan Holder, Shin-ichi Usami, Zhengyi Chen, Pu Dai, Jeffrey Holt, Rick Nelson, Byung Yoon Choi, Eliot Shearer, Richard J. H. Smith, Ronald Pennings, Xue Zhong Liu
Institutions: University of Miami, Radboud University Medical Center, University of Iowa, Florida International University, Boston Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, University Medical Center Groningen, Maastricht University Medical Centre, Maastricht University, Leiden University Medical Center, Erasmus MC, Bethlehem University, University of Washington, Vanderbilt University, Shinshu University, Massachusetts Eye and Ear Infirmary, Harvard University, Chinese PLA General Hospital, Indiana University Indianapolis, Indiana University School of Medicine, Seoul National University Bundang Hospital
Language: English
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,090
Awards: G1557911763, G1649372110, Implementing genomic medicine in clinical care of deaf patients, G4162735734, Genetically Mediated Hair Cell Degeneration in 3D Inner Ear Organoids, Molecular Genetics on Non Syndromic Hearing Loss (NSHL), Non-Syndromic Hearing Loss A Collaborative Study, G673180586, Development of CRISPR/Cas9-based exon-skipping strategies for the treatment of USH-associated deafness, Boston Children's Hospital/HMS Intellectual and Developmental Disabilities Research Center, Optimizing Genetic Testing for Deafness for Clinical Diagnostics, Spiral Ganglion Health: from Genomics to Gene Therapy
OpenAlex ID: W4396553634