The genetics of otosclerosis
Four genes for otosclerosis have been mapped to chromosomes 15q25-q26 (OTCS 1), 7q34-q36 (OTCS 2), 6p21.3-22.3 (OTCS 3) and 3q22-24 (OTSC5). None of the genes have been cloned. Further, an association between otosclerosis and the type I collagen genes (implicated in osteogenesis imperfecta) has been suggested. The aim of the present study was to determine whether any further evidence of linkage at the known otosclerosis gene loci exists. Isolated cases, sib-pairs and nuclear families with otosclerosis were ascertained and clinically assessed. Twenty-five families with otosclerosis were identified in which at least two of their members were affected. Majority of the families revealed an autosomal dominant pattern of inheritance. Genetic linkage analysis was carried out in all these families, using microsatellite markers for the known otosclerosis gene loci on chromosomes 15q25-q26, 7q34-q36 and 6p21.3-22.3 and at the COL1A1 and COL1A2 gene loci. Statistically significant exclusion of the COL1A1 locus was demonstrated in one family, as linkage analysis revealed negative LOD scores with values lower than -2. There was supporting evidence for linkage of the disease in the OTSC1, OTSC2, OTSC3, and COL1A2 loci in few families. Maximum LOD score value (+1.75) was obtained using multipoint linkage analysis in OTSC2 locus. However, most of the families revealed negative LOD score values but they were not low enough (<-2) to formally exclude linkage to these regions. Additional techniques used in complex genetics will be required to identify genes involved in the otosclerosis pathology. Knowledge of these genes could lead to substantial improvements in our ability to diagnose and possible even prevent this type of hearing deterioration.