A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa.
Usher syndrome is an inherited disorder that is characterized by hearing impairment (HI), retinitis pigmentosa, and in some cases vestibular dysfunction. Usher syndrome type IIa is caused by mutations in USH2A. HI in these patients is highly heterogeneous and the present study evaluates the effects of different types of USH2A mutations on the audiometric phenotype. Data from two large centres of expertise on Usher Syndrome in the Netherlands and Sweden were combined in order to create a large combined sample of patients to identify possible genotype-phenotype correlations.



A retrospective study on HI in 110 patients (65 Dutch and 45 Swedish) genetically diagnosed with Usher syndrome type IIa. We used methods especially designed for characterizing and testing differences in audiological phenotype between patient subgroups. These methods included Age Related Typical Audiograms (ARTA) and a method to evaluate the difference in the degree of HI developed throughout life between subgroups.



Cross-sectional linear regression analysis of last-visit audiograms for the best hearing ear demonstrated a gradual decline of hearing over decades. The congenital level of HI was in the range of 16-33 dB at 0.25-0.5 kHz, and in the range of 51-60 dB at 1-8 kHz. The annual threshold deterioration was in the range of 0.4-0.5 dB/year at 0.25-2 kHz and in the range of 0.7-0.8 dB/year at 4-8 kHz. Patients with two truncating mutations, including homozygotes for the common c.2299delG mutation, developed significantly more severe HI throughout life than patients with one truncating mutation combined with one nontruncating mutation, and patients with two nontruncating mutations.



The results have direct implications for patient counselling in terms of prognosis of hearing and may serve as baseline measures for future (genetic) therapeutic interventions.
Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: bas.hartel@radboudumc.nl.
Bas P
BP
Hartel
Swedish Institute for Disability Research (SIDR) Linköping, Sweden; Audiological Research Centre, Örebro University Hospital, Örebro, Sweden; School of Medicine and Health, Örebro University, Örebro, Sweden.
Maria
M
Löfgren
Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Patrick L M
PL
Huygen
Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Iris
I
Guchelaar
Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Nicole
N
Lo-A-Njoe Kort
The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Audiology, Göteborg, Sweden; Hearing and Deafness Activities Organization, Habilitation & Health, Göteborg, Sweden.
Andre M
AM
Sadeghi
Department of Otorhinolaryngology, Donders Institute for Brain, Cognition and Behaviour, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Erwin
E
van Wijk
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark; Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Bispebjerg Hospital/Rigshospitalet, Copenhagen, Denmark.
Lisbeth
L
Tranebjærg
Department of Otorhinolaryngology, Donders Institute for Brain, Cognition and Behaviour, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Hannie
H
Kremer
Department of Otolaryngology, Molecular Otolaryngology, and Renal Research Laboratories, University of Iowa, Iowa City, IA, USA.
William J
WJ
Kimberling
Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Cor W R J
CW
Cremers
Swedish Institute for Disability Research (SIDR) Linköping, Sweden; Audiological Research Centre, Örebro University Hospital, Örebro, Sweden; School of Medicine and Health, Örebro University, Örebro, Sweden.
Claes
C
Möller
Department of Otorhinolaryngology, Donders Institute for Brain, Cognition and Behaviour, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Ronald J E
RJ
Pennings
D000293:Adolescent; D000328:Adult; D000368:Aged; D001299:Audiometry; D001301:Audiometry, Pure-Tone; D001309:Auditory Threshold; D003430:Cross-Sectional Studies; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006309:Hearing; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands; D010641:Phenotype; D012189:Retrospective Studies; D013548:Sweden; D052245:Usher Syndromes / Q000235:genetics* / Q000503:physiopathology*; D055815:Young Adult
D016326:Extracellular Matrix Proteins; C112735:USH2A protein, human