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A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa
Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
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.
Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
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2016 (English)In: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 339, 60-68 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: 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.

Design: 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.

Results: 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.

Conclusions: 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.

Place, publisher, year, edition, pages
Amsterdam, Netherlands: Elsevier, 2016. Vol. 339, 60-68 p.
National Category
Otorhinolaryngology Neurology
Research subject
Oto-Rhino-Laryngology; Neurology
Identifiers
URN: urn:nbn:se:oru:diva-50977DOI: 10.1016/j.heares.2016.06.008ISI: 000383944300007PubMedID: 27318125Scopus ID: 2-s2.0-84975809636OAI: oai:DiVA.org:oru-50977DiVA: diva2:940572
Note

Funding Agencies:

Innovatiefonds B13-200-2677

Fonds Nuts-Ohra 1303-009

Heinsius Houbolt Fonds

Netherlands Organisation for Health Research and Development (ZonMW Klinisch Fellowship) 90700388

Foundation Fighting Blindness C-CMM-0811-0547-RAD03

Netherlands Organisation for Scientific Research Veni-016.136.091

Netherlands Organisation for Health Research and Development (ZonMW E-rare grant) 40-42900-98-1006

Available from: 2016-06-21 Created: 2016-06-21 Last updated: 2017-10-17Bibliographically approved

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CiteExportLink to record
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