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I. Ebermann, I. Lopez, R. Pigeon, C. Brown, R. K. Koenekoop, H. J. Bolz; Elucidation of the Genetic Basis of Usher Syndrome Type 2 in Canadians of French Origin: Implications for Diagnostic and Clinical Management. Invest. Ophthalmol. Vis. Sci. 2008;49(13):460. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To explore the genetic basis of Usher syndrome type 2 (USH2) in Canadians of French origin, to describe novel USH2C mutations in a male and to explore the genetic link between Acadians and French Canadians. Significant congenital hearing loss affects at least one child in 1000 and results in profound medical and social consequences. About 10% of the deaf population develop USH, a recessively inherited condition with strong genetic heterogeneity. In USH patients, hearing loss is complicated by additional retinal degeneration with onset in the first (USH1) or second (USH2) decade. In most populations, diagnostic testing for USH2 is complicated by a multitude of mutations, mostly in the large USH2A gene.
DNA samples from nine USH2 families originating from different regions of Quebec and from New Brunswick (the former Acadia) were screened by direct sequencing for mutations in the three known USH2 genes (USH2A, VLGR1b, DFNB31) We then performed haplotype analyses for the USH2A locus.
USH2A mutations were identified in eight patients (88.9%). A two-basepair deletion in the USH2A gene, c.4338-4339delCT, accounts for 10/18 disease alleles (55.6%). Six additional heterozygous USH2A mutations were found. In one male patient, we identified two novel mutations in the USH2C gene, VLGR1b.
A founder mutation in the USH2A gene, c.4338-4339delCT, is the predominant cause of USH2 in Canadians that descend from French settlers. This mutation has previously been reported in two Acadians, and it was also found in homozygous state in all three Acadians of our sample. Our USH2 haplotype analyses reveal that the populations of Quebec and former Acadia overlap significantly, as we have previously shown with the haplotypes of French-Canadian USH1 mutations. With a limited number of molecular tests, it will now be possible in these populations to estimate whether a congenitally hearing-impaired child will develop additional retinal disease in later life due to an USH2 gene mutation - with important implications for clinical management and therapeutic intervention before onset of visual problems. In addition, this is the first report of a male USH2C patient which refutes the hypothesis that this subtype may be lethal in males.
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