Genetic contributions to familial Ménière's disease: a systematic review.

backgroundMeniere's disease (MD) is a fluctuating vestibulocochlear disorder with an unknown cause. Familial clustering occurs in 8-10% of cases, suggesting a genetic contribution, but the underlying mechanisms remain unclear. This systematic review synthesizes all sequencing studies in familial MD and evaluates the strength of evidence supporting candidate genes.

methodsA PRISMA-guided search of PubMed and Embase (June 2024) identified original human genetic studies in families with MD diagnosed according to Bárány Society or AAO-HNS criteria. Two reviewers independently screened studies, extracted data, and reassessed variants using ACMG/AMP guidelines. Risk of bias was evaluated with the Newcastle-Ottawa Scale.

resultsNine studies met inclusion criteria, reporting 29 rare variants across 17 genes in 194 families. Most variants (24/29) were missense; the remainder included three nonsense variants and two frameshift deletions. Seventeen variants were classified as pathogenic or likely pathogenic in the original studies. Evidence for segregation was limited, and functional validation was not always available. Some genes (e.g., OTOG, MYO7A, TECTA, DMXL2) have known roles in auditory function, but the associated phenotypes differ markedly from MD and lack fluctuating hearing loss or episodic vertigo. Most other genes had no prior link to inner-ear disease. Overall, the methodological heterogeneity, small family sizes, and incomplete segregation data greatly limit the strength of causal inference.

conclusionCurrent evidence does not support a single monogenic cause of familial MD. Findings indicate marked genetic heterogeneity. Given that only nine studies met the inclusion criteria, the current evidence base remains limited, and the conclusions of this review should be considered provisional and hypothesis-generating rather than definitive. Larger genome-wide studies, knock-in models, and patient-specific cochlear or vestibular organoids are needed to validate candidate genes and clarify pathogenic mechanisms.