Dissecting the genome in Ménière disease: a review

Ménière disease (MD) is a complex inner ear disorder characterized by episodic vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. Despite its prevalence across European and Asian populations, along with five clinical subtypes with variable phenotypes and comorbidities, the molecular underpinnings of MD pathogenesis remain under investigation. This review aims to comprehensively summarize the genomic, epigenomic, and transcriptomic insights into MD, highlighting how these molecular layers contribute to disease susceptibility, progression, and phenotypic variability. Sporadic MD accounts for most diagnoses, where multifactorial mechanisms involving pathogenic rare variants, epigenetic modifications, and immune-related pathways contribute to disease risk. We also elucidate the genetic contribution of familial MD, in which inherited variants, primarily in genes involved in the extracellular structures of sensory epithelia and the stereocilia links of sensory cells, contribute to autosomal dominant, recessive, or digenic inheritance models. Furthermore, we explore the current use of animal models in validating gene pathogenicity. By integrating findings across multi-omics studies, this review emphasizes that MD is a polygenic and heterogeneous inherited disorder, with a spectrum of related conditions with common and distinct molecular origins. Understanding molecular mechanisms involving genetic and epigenetic factors is promising for biomarker discovery and future therapeutic interventions.