CLINICAL STUDIES OF USHER SYNDROME

Father Flanagan'S Boys'Home, Boys Town NE

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Abstract

The frequency of childhood deafness is estimated at 1/1000. At least half of this hearing loss is genetic and about 80% of the genetic hearing loss is recessive non-syndromic. Our goal has been to determine the relative frequencies of the different forms of NSRHL and to examine whether there are differences in the clinical manifestations of non-syndromic hearing loss. The most common form of this type of hearing loss, DFNB1 was found to be caused by mutations in GJB2, the gene encoding connexin 26. Almost half of recessive non-syndromic hearing loss in European and American populations is due to mutations in GJB2. Genetic studies indicate that the other half of recessive non-syndromic hearing loss is caused by many genes, each individually responsible for a small fraction of NSRHL. The loci for nineteen of these genes have been localized. Heterogeneity studies indicate as many as 100 additional loci remain to be discovered. We have established a resources of NSRHL families primarily of American origin. This resource has proven its value in defining the spectrum and frequency of GJB2 (Cx26) mutations in the American population and their clinical profile. We propose to expand this collection with both American families and families collected through our collaborators in Japan, Russia, and Europe. Our initial assessment of these families will be for the common Cx26 mutations. Families whose hearing loss is not caused by Cx26 mutations will be assayed for linkage to other know loci and subjected to whole genome search for linkage if necessary and appropriate. Cx26 families will be further studied to document the progressive hearing loss. Cx26 families will be analyzed for linkage disequilibrium and the mutational frequency of 35delG to determine the origin of the 35delG mutation: mutational hot spot or common founder. A control and 35delG heterozygote population will be studied to define the phenotype associated with the 35delG heterozygote Families mapping to and not excluded from known hearing loss genes will be analyzed for mutations by sequence analysis and or heteroduplex analysis. Candidate genes from regions with known linkage will be evaluated for mutations.