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Jose Antonio Lopez-Escamez

Jose Antonio Lopez-Escamez MD, PhD

Otology & Neurotology Group CTS 495, Department of Genomic Medicine, Centre for Genomics and Oncological Research (GENyO)

Department of Otolaryngology, Instituto de Investigación Biosanitaria Ibs.GRANADA, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada, Spain.

Topic:Advances in genetics of familial and sporadic Meniere’s disease

Meniere's disease (MD) is considered a complex disorder of the inner ear associated with tinnitus, episodes of vertigo and fluctuating sensorineural hearing loss (SNHL) that may involve low and medium frequencies or all frequencies and that it usually progresses to moderate or severe SNHL. The vestibular function also fluctuates in most patients and the syndrome has been attributed to an accumulation of endolymph in the cochlear duct (endolymphatic hydrops), but this condition is also observed in patients with isolated SNHL. The current diagnosis of MD is based on the phenomenological association of clinical symptoms and the demonstration of SNHL during the vertigo attacks, but different clinical variants have been reported according to several predictors such as , autoimmune disorder or familial history of MD.

Five clinical subgroups of patients with MD are now distinguished and only half of the patients show the isolated cochlea-vestibular syndrome without migraine, autoimmunity or familial history of MD (MD type 1).

Several evidences support a genetic contribution to MD, including the differences observed in the prevalence according to the ethnic background, and the strong familial aggregation found in European and Asian populations in multiplex families with autosomal dominant inheritance. The genetic underpinnings of MD include some rare monogenic forms in isolated families and a polygenic contribution in most familial and sporadic cases. So, familial MD has been reported in 6-8% of sporadic cases and several genes have been described in single Spanish families with MD including FAM136A, DTNA, PRKCB, SEMA3D and DPT, suggesting genetic heterogeneity. Multiplex rare missense variants (minor allelic frequency <0.05) in OTOG gene have been reported in 33% of familial MD, suggesting multiallelic inheritance. Moreover, the genetic of sporadic MD is more complex and it involves multiplex and novel rare variants in several SNHL genes such as GJB2, USH1G, SLC26A4, ESRRB, and CLDN14 and “axonal-guidance signalling genes” such as NTN4 and NOX3. Moreover, singleton and rare variants have been reported in non-familial cases in “familial MD genes” such as FAM136A, DTNA and DPT in East Asian population.

According to the genetic architecture of MD, we should consider this condition as a set of rare genetic disorders with a core phenotype showing clinical heterogeneity. The genetic model in sporadic cases points to a polygenic condition that include singleton and rare variants with a large effect size in coding regions and common non-coding variants such as rs4947296 with regulatory effects in the inflammatory response that may explain the variable expressivity in the phenotype.