Exploring the genetic landscape of otosclerosis: current understanding and future perspectives

Otosclerosis is characterised by abnormal bone remodelling in the otic capsule, leading to progressive hearing loss. Unlike many genetic disorders, the causative genes for otosclerosis remain largely unidentified despite extensive research using linkage analysis and genome-wide association studies (GWAS). Inheritance patterns in otosclerosis suggest a multifactorial model involving genetic predisposition and environmental triggers, a model applied to other common diseases, such as age-related hearing loss, coronary artery disease, and Alzheimer’s disease. Linkage analysis has identified nine loci associated with monogenic forms of otosclerosis, yet the specific causative genes and variants remain elusive. Promising insights have emerged from GWAS, with strong associations identified for novel candidate regions, including the RELN gene. Recent studies using next generation sequencing have identified several candidate genes such as SERPINF1, ACAN, and MEPE. SERPINF1, encoding pigment epithelium-derived growth factor, is linked to regulation of angiogenesis in bone remodelling. ACAN, associated with the OTSC1 locus, encodes aggrecan a crucial component of the extracellular matrix in cartilage, showing a range of variants with varied effect sizes and frequencies. MEPE, involved in bone homeostasis, has been significantly associated with otosclerosis in large family-based and case-control cohorts. While considerable progress has been made in identifying potential genetic contributors, the precise genetic architecture of otosclerosis remains to be fully elucidated. An integrated approach combining genetic data and clinical information, such as audiometric testing and temporal bone imaging, is essential for a comprehensive understanding of otosclerosis.