The genetics of otosclerosis: pedigree studies and linkage analysis.

Otosclerosis is one of the commonest causes of hearing loss in adults. The hereditary nature of the disease has been acknowledged for over a century but the precise genetic basis of the disorder has as yet not been characterised. It is currently recognised that familial otosclerosis exhibits autosomal dominant inheritance with variable penetrance and expression. More recently, family linkage studies have identified three chromosomal regions that can be ascribed to this disorder: otosclerosis 1 on chromosome 15, otosclerosis 2 on chromosome 7 and a third locus on chromosome 6. The genes responsible for the disease within these regions remain to be defined. The work presented in this paper firstly examined the familial nature of the disease in a cohort of individuals that had undergone surgery for otosclerosis. Following detailed ascertainment, pedigrees were constructed for subsequent genetic analysis. The laboratory analysis included linkage analysis of the candidate region on the long arm of chromosome 15, linkage analysis of the aggrecan protein gene within the 15q region and linkage analysis to chromosome 7q. The pedigree studies confirmed the hereditary nature of otosclerosis and the recognised mode of inheritance. Linkage to the chromosome 15 locus, the candidate aggrecan gene and the chromosome 7 locus was excluded, confirming that otosclerosis exhibits locus heterogeneity.