The genetic aetiology of otosclerosis in the population of Newfoundland and Labrador

Abdelfatah, Nelly (2014) The genetic aetiology of otosclerosis in the population of Newfoundland and Labrador. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Background Otosclerosis is a common form of conductive and mixed hearing loss in Caucasian populations, with an estimated prevalence of 0.3-0.4%. Since 1998, eight loci have been mapped to otosclerosis in families with apparent autosomal dominant (AD) otosclerosis but none of the causative genes have been identified. Objective As no otosclerosis gene has yet been identified, the main objective of this thesis was to identify otosclerosis-disease causing genes by studying Newfoundland (NL) families. Methods Families with familial otosclerosis were identified and chracterized clinically. Those which fit the diagnostic criteria for otosclerosis were recurited for this study. Molecular genetic analyses of these families were carried out by genotyping, haplotyping, Sanger sequencing of candidate genes in linked regions and exome sequencing. Results One Family (2081) was solved through identification of a pathogenic variant (FOXL1c.976_990hetdel) in the FOXL1 gene at chromosome (Chr) 16q that was present in all affected individuals. The 15 base pair (bp) deletion was also identified in a second family from Ontario (ON) and the possible pathways involving FOXL1 in the pathogenesis of otosclerosis were suggested. In the second otosclerosis family, three III candidate variants were identified through exome sequencing of the candidate regions under a dominant model. Conclusion I have identified the first otosclerosis gene, FOXL1, a transcription factor involved in the disease pathogenicity. I also identified three possible candidate mutations for a second otosclerosis family. This finding will have a major impact on molecular genetic studies of other otosclerosis families and it will allows for genetic counselling and the possibility for gene therapies in the future.

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