Doctor of Philosophy
Health and Rehabilitation Sciences
Stanton, Susan G.
Otosclerosis is a relatively common hearing loss disorder characterized by abnormal bone growth in the otic capsule leading to stapes fixation. In approximately half of cases, otosclerosis is inherited as an autosomal dominant trait. Typically, gene discovery efforts rely on surgical confirmation, audiometry and occasionally acoustic reflexes to identify affected cases of otosclerosis within families, requiring that the otosclerosis was at an advanced stage to be detected. This makes it difficult to identify individuals with early otosclerosis. The use of advanced phenotyping to identify cases of otosclerosis was tested in an Ontario otosclerotic population as well as in two large Newfoundland families, one with otosclerosis due to a newly discovered deletion in the FOXL1 gene. Family history questionnaires revealed that approximately two-thirds of Ontario probands had a significant family history of non-congenital hearing loss with almost half of those probands reporting another family member with otosclerosis. Furthermore, all Ontario probands were screened for the FOXL1 deletion identified in the NL family, with one testing positive, providing evidence that FOXL1 may underlie cases of otosclerosis in other populations.
The otosclerotic phenotype of prospective data obtained in a surgically-confirmed Ontario cohort was quite variable with 30% of subjects presenting with unilateral otosclerosis and 9% presenting with sensorineural hearing loss (SNHL) in their non-surgical ear. Results suggest that distortion product otoacoustic emissions and acoustic reflex thresholds are absent in all surgical ears, SNHL ears and ears with a conductive hearing loss. To further enhance the advanced phenotyping of otosclerosis, power absorbance (PA) was analyzed to determine its utility as a phenotyping tool. Results suggest that PA has a valid test-retest reliability, but that instrument and stimulus effects are present.
Advanced phenotyping was used to develop a predictive model for FOXL1-associated otosclerosis suggesting a progressive mixed hearing loss. Phenotyping in a second large, non-FOXL1 family identified members with suspected early disease progression. Early identification of otosclerosis, without having to wait for a surgical confirmation, will aid future gene discovery research. Furthermore, insights gained from advanced phenotyping in sub-clinical gene carriers can provide a deeper understanding of the natural history of otosclerosis.
Summary for Lay Audience
Otosclerosis is a heritable bone disorder characterized by abnormal bone growth within the ear occurring later-in-life. When the abnormal bone growth invades the middle ear, it results in a conductive hearing loss, however, it can cause a sensorineural hearing loss if the abnormal bone growth invades the cochlea. Recently, the first causative gene (FOXL1) for the disorder was identified in a large Newfoundland family. In an Ontario otosclerosis population, FOXL1 was screened, and one subject was identified with the mutation, providing evidence that the FOXL1 mutation occurs outside of the family where it was originally found. Advanced phenotyping, using clinical tools to measure the physiological changes of a trait, was used in an Ontario otosclerotic population, as well as in two large families with otosclerosis. Results from the Ontario otosclerotic population confirmed that the clinical presentation of otosclerosis is variable. Subjects had hearing loss in one or both ears, as well as the conductive or sensorineural form of the hearing loss, or a combination of the two referred to as a mixed hearing loss. A normative study was conducted to investigate whether, power absorbance (PA), a measure of how sound can travel through the middle ear, is a valid phenotyping tool for otosclerosis. Results suggest that PA is different in otosclerotic ears compared to typical ears and could be used for future phenotyping studies. Advanced phenotyping of a large Newfoundland family with family members carrying the mutation in FOXL1 gene suggests that the clinical features of otosclerosis can present quite variably even when the same gene is responsible for the hearing loss. A predictive model of otosclerosis caused by FOXL1 was also created which suggests a progressive mixed hearing loss in affected gene carriers. Finally, advanced phenotyping was conducted in a separate large otosclerotic Newfoundland family of unknown genetic cause. Results suggest that using an advanced phenotyping approach has the possibility of improving future genetic and clinical studies of otosclerosis by possibly identifying early indicators of otosclerosis progression.
Lucas, Matthew B., "Advanced Phenotyping of Otosclerosis in an Ontario Population and Two Large Newfoundland Families" (2020). Electronic Thesis and Dissertation Repository. 6986.