Canadian researchers recently published their discovery of FOXL1, the first causative gene for otosclerosis, a common cause of conductive and mixed hearing loss in adults. This discovery was the result of a 10-year collaboration between Western University (London, Ontario) and Memorial University (St John’s, Newfoundland, and Labrador) and was funded by Canadian Institutes of Health Research and Genome Canada.

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The study was designed by Nelly Abdelfatah, PhD candidate, and Dr Terry-Lynn Young, faculty of medicine, Memorial University, Matthew Lucas, PhD candidate, and Dr Susan G. Stanton, faculty of health sciences, Western University, and published in Human Genetics. An article detailing the research appears on the Western University website.

The researchers identified a causative gene, FOXL1, for autosomal dominant otosclerosis in an extended family in the province of Newfoundland and Labrador, Canada. The same mutation was also identified in an unrelated case of otosclerosis in the province of Ontario, Canada.

The research discovery comes through collaborative work between Memorial’s Faculty of Medicine and Faculty of Science, and the National Centre for Audiology in the Faculty of Health Sciences at Western University.

Gene Discovery Challenge

Inherited otosclerosis is an adult-onset dominant condition, which makes it trickier to chase down genetically. The challenge is finding a single gene mutation passed down through one parent, rather than a pair of mutations inherited from both parents, as occurs with recessive forms of hearing loss. Through traditional gene mapping and newer sequencing methods, however, a large family with autosomal dominant otosclerosis was identified, and their DNA analyzed to find the segment with a unique DNA sequence only present in those with the condition.

Another complication for gene discovery was the delayed onset of this condition, which typically appears between the third and fifth decades of life. A conservative diagnosis of the disease was also necessary in order to hone in on those who definitely had otosclerosis, instead of other forms of adult hearing loss. Being able to work with the founder population of Newfoundland, with large families and many affected adult family members provided a significant advantage.

Clinical Impact

In otosclerosis, bone growth causes the stapes, one of the tiny bones in the middle ear, to become fixed in place. As a result, it cannot vibrate and conduct sound waves to the inner ear, resulting in hearing loss. In some individuals with more severe otosclerosis, the bone surrounding the inner ear can also be involved. There is no current cure for otosclerosis, but many patients use hearing aids or have surgery to replace the stapes bone with a prothesis. The surgery does not always work to restore hearing, however, and the condition gets worse over time.

“Discovering a gene responsible for otosclerosis will help us to understand the biology of this bone disease, and will pave the way to finding new drugs and therapies to treat and potentially prevent otosclerosis,” Stanton said.

“I think in terms of basic research, the mutated FOXL1 gene encodes the first identified protein involved in the repression of bone remodeling in the ear. This will potentially have a huge impact now that scientists know the biological pathways involved in bone remodeling specifically in the pathology of otosclerosis” said Young. Down the road, the research could lead to therapies that target the specific proteins affected.

Finding a causative gene for the condition also paves the way for a genetic test, so those at risk of developing this type of otosclerosis could be identified early, even before their hearing declines significantly, which could be important as new treatments become available.

Further Research

The research team is currently looking for other genes related to hearing disorders, including otosclerosis, in other families, in hopes of mapping them with the same techniques used in this study. Families with a history of otosclerosis, or other types of hearing dysfunction, who are interested in participating in future research can reach out to Young or Griffin at Memorial University in Newfoundland, or Stanton at Western University in Ontario.

“The more families, the better,” Young said.

Young and Stanton expect that co-operation with other Memorial researchers and collaboration with those at Western will continue. At Memorial University, Valerie Booth and her team in the faculty of science played a role in looking at the structure of the mutated protein. Drs. Curtis French, Faculty of Medicine, and Ahmed Mostafa, a postdoctoral fellow with Young, looked at how the gene mutation affected the way the protein malfunctioned in cells; French and his team are developing zebrafish models of FOXL1. Lucas, PhD candidate at Western in the faculty of health sciences, did the phenotyping work on the Newfoundland family, and phenotyping and genetic screening of cases from Ontario. Research audiologist Anne Griffin at the Centre for Genomics-Based Research and Development in Hearing Science in Newfoundland, and otolaryngologists Dr Lorne Parnes and Dr Sumit Agrawal from the Faculty of Medicine at Western University and Dr Tony Batten from St John’s added their clinical expertise.

Original Paper: Abdelfatah N, Mostafa AA, French CR, et al. A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene. Human Genetics. 2021. DOI:

Source: Western University, Human Genetics