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Title
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Genotype-phenotype correlation study in p.Pro51Ser variant carriers in COCH causing DFNA9
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Author
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Abstract
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| DFNA9 is an autosomal dominant hereditary hearing disorder associated with vestibular deterioration with a late onset of symptoms. Many variants in COCH have been identified, however, the c.151C>T, p.Pro51Ser is highly prevalent in the Low Countries. The clinical characteristics of this condition were based on genetic linkage studies of some 15 years ago. However, nowadays, new clinical vestibular tools permit more detailed observation of the progression of the vestibular deterioration at different compartments and at different frequency range of the vestibular organ. Since the last several years, tremendous efforts are being displayed to develop new therapeutic options, such as vestibular implants and genetic therapy, for which a better knowledge of the natural course of DFNA9 has become essential to define the most optimal therapeutic window. A prospective multi-centric cross-sectional study, conducted in Antwerp and Hasselt, including 111 Belgian & Dutch p.Pro51Ser variant carriers, showed the following results: 1) the hearing thresholds at 8 kHz were already beyond age-referenced limits in the youngest age group (18-25 years), 2) this was followed by the decline of caloric response (35 years on average) and C-VEMPs (31 years). 3) The hearing frequencies higher than 2 kHz all started to deteriorate at about 34-38 years of age, whereas the lower frequencies started their decline ten years later. 4) The vestibulo-ocular reflexgains, which are obtained with high angular acceleration video head impulse test (vHIT), were the last to deteriorate (end of 4th & early 5th decade). Imaging of DFNA9 patients showed typical features like focal sclerosis or T2-weighted signal loss in semicircular canals (SCC) of p.Pro51Ser carriers that had reached advanced stages of oto-vestibular deterioration. These lesions seemed to correlate with lower caloric and vHIT function. These findings suggest an (auto)immune reaction as a result of accumulation of misfolded mutant cochlin in the inner ear and ampullae of the SCC, with fibrosis and late-onset calcification. Until 2018, all known COCH variants had autosomal dominant trait, however, we identified a new COCH variant with an autosomal recessive trait, causing congenital hearing loss (DFNB110). Since adult heterozygous carriers in that family all showed normal hearing and balance function, this suggests haploinsufficiency is not the cause of hearing disorder, but rather the dominant negative trait of these new variants. These new insights are useful in future research for new treatment options in DFNA9 patients. |
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Language
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English
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Publication
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2021
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Volume/pages
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341 p.
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Note
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Van Rompaey, Vincent [Supervisor]
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Van Camp, Guy [Supervisor]
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Full text (open access)
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