A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa

• Published in: Hearing research Vol. 339; pp. 60 - 68
• Main Authors: Hartel, Bas P., Löfgren, Maria, Huygen, Patrick L.M., Guchelaar, Iris, Lo-A-Njoe Kort, Nicole, Sadeghi, Andre M., van Wijk, Erwin, Tranebjærg, Lisbeth, Kremer, Hannie, Kimberling, William J., Cremers, Cor W.R.J., Möller, Claes, Pennings, Ronald J.E.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2016
• Subjects: Adolescent; Adult; Aged; Audiometry; Audiometry, Pure-Tone; Auditory Threshold; Cross-Sectional Studies; Extracellular Matrix Proteins - genetics; Female; Gastroenterologi; Gastroenterology and Hepatology; Genetic Association Studies; Genotype; Hearing; Humans; Linear Models; Male; Middle Aged; Mutation; Netherlands; Neurologi; Neurology; Oto-rhino-laryngologi; Oto-Rhino-Laryngology; Oto-rino-laryngologi; Otorhinolaryngology; Phenotype; Retrospective Studies; Reumatologi och inflammation; Rheumatology and Autoimmunity; Sweden; Usher Syndromes - genetics; Usher Syndromes - physiopathology; Young Adult
• ISSN: 0378-5955; 1878-5891; 1878-5891
• DOI: 10.1016/j.heares.2016.06.008

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. •There is variability in the phenotypic presentation in Usher syndrome type IIa.•Hearing loss in Usher syndrome type IIa is progressive.•Two truncating mutations in USH2A result in more severe and progressive hearing impairment.