Giselle Bianco-Bortoletto

The MDAtlas is a crowdsourcing initiative to provide an open access resource with multiomic dataset about Meniere Disease (MD) -a debilitating audiovestibular disorder- to the scientific/medical community. The platform ( https://multiomic-md.sydney.edu.au ) integrates anonymised genomic, transcriptomic and epigenomic datasets from several MD cohorts with diverse ancestry through the MD multiomic Agreggation Consortium (MD-MAC), helping users investigate common and rare genomic variability, immune cell gene expression, and DNA methylation patterns involved in these conditions. MDAtlas supports secure data upload, advanced filtering, and easy downloading, allowing researchers to compare datasets across populations and discover new disease mechanisms or biomarkers for diagnosis and therapy. By providing interactive tools and harmonized data, MDAtlas accelerates scientific progress and collaboration in hearing and vestibular research.

Meniere disease (MD) is an inner ear disorder characterised by episodic vertigo, tinnitus, and sensorineural hearing loss. Previous sequencing studies have identified rare mutations in 16 genes expressed in hair cells, many of which are involved in maintaining the structure and stability of stereocilia. Experimental evidence supports that noise-induced hearing loss is associated with structural damage in the hair cell stereocilia. We hypothesise that rare variants in genes expressed in hair cell stereocilia may predispose individuals to MD with occupational noise exposure. To explore this, we analysed whole exome sequencing data from MD patients with documented histories of occupational noise exposure. A rare missense variant chr22:37769343C>T in the TRIOBP gene was identified in three individuals (OR=1,846 (203-8192), p=3.39x10 ^-5 ). In silico protein modelling suggests this variant (p.R2273C) interacts with the Actin C chain, potentially affecting cytoskeletal integrity in hair cells. Immunolabelling confirmed TRIOBP expression in the stereocilia rootlets of cochlear and vestibular hair cells, supporting its structural function in both sensory epithelia. Furthermore, retrieved MD single-cell ATAC-seq data revealed reduced chromatin accessibility at the RFX3 transcription factor locus, suggesting a transcriptional TRIOBP downregulation. Our results support that occupational noise exposure may trigger MD in the carriers of TRIOBP mutations.

Ménière’s Disease (MD) is a chronic inner ear disorder defined by recurring episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus, and/or fullness in the ear. Its prevalence varies by region and ethnicity, with scarce epidemiological data in the Brazilian population. Although most MD cases are sporadic, familial MD (FMD) is observed in 5% to 20% of European cases. Through exome sequencing, we have found a rare missense variant in the OTOG gene in a Brazilian individual with MD with probable European ancestry (chr11:17599671C>T), which was previously reported in a Spanish cohort. Two additional rare missense heterozygous OTOG variants were found in the same proband. Splice Site analysis showed that chr11:17599671C>T may lead to substantial changes generating exonic cis regulatory elements, and protein modelling revealed structural changes in the presence of chr11:17599671C>T, chr11:17576581G>C, and chr11:17594108C>T, predicted to highly destabilize the protein structure. The manuscript aims to replicate genes previously reported in a Spanish cohort, and the main finding is that a Brazilian patient with MD also has variants previously reported in familial MD, supporting OTOG as the most frequently mutated gene in MD.

Menière’s disease (MD) is an inner ear disorder characterised by episodes of vertigo, sensorineural hearing loss and tinnitus linked to autoinflammation and/or type 2 immune response. We hypothesise that rare variation in immune response genes could drive the autoinflammatory phenotype in MD. We retrieved differentially expressed genes (DEG) from single-cell RNAseq and epigenomic datasets to search for rare variants in the MD exome (N = 454) and genome (N = 511) sequencing datasets. The variant chr1:10374335 C > T in the KIF1B gene was found in three MD unrelated individuals and was predicted to be likely pathogenic. According to differential transcript usage, transcript ENST00000622724.3 was found in MD samples, but absent in controls. Furthermore, this variant may influence splicing through the generation of exonic enhancers and silencers, potentially changing transcription factor binding at the promoter. These findings support that this KIF1B gene rare variant is associated with the MD autoinflammatory phenotype and may up-regulate its expression in monocytes.

Ménière’s Disease (MD) is a chronic inner ear disorder defined by recurring episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus, and/or fullness in the ear. Its prevalence varies by region and ethnicity, with scarce epidemiological data in Brazilian population. Although most MD cases are sporadic, Familial MD (FMD) is observed in 5% to 20% of European cases. By exome sequencing, we have found a rare missense variant in the OTOG gene in a Brazilian MD individual with probable European ancestry (chr11:17599671C>T), which was previously reported in a Spanish cohort. Two additional rare missense heterozygous OTOG variants were found in the same proband. Splice Site analysis showed that chr11:17599671C>T may lead to substantial changes generating exonic cis regulatory elements, and protein modelling revealed structural changes in the presence of chr11:17599671C>T, chr11:17576581G>C and chr11:17594108C>T, predicted to highly destabilize protein structure. These findings indicate that missense variants may have an additive effect leading to an unstable Otogelin and support OTOG gene as a key player in the MD pathophysiology.