Mai T. Pham

The genetic basis underlying the co-occurrence of tinnitus and mild cognitive impairment (MCI) remains unknown. Adults with chronic tinnitus from a European cohort were classified into MCI (n=75) and non-MCI (n=201) groups, and rare variant distributions were assessed using gene burden analyses. Approximately one-fourth of individuals with chronic tinnitus exhibited MCI in their early fifties. Rare loss-of-function variants in PRKRA were identified in 18.6% of MCI patients, including a recurrent ∼3kb deletion in 14 individuals (OR=513.86, 95% CI [224.34-1177.02], adjusted p -value = 1.04E-48). These carriers reported tinnitus onset approximately eight years before MCI was observed. Cognitive impairment was linked to tinnitus, but not to hyperacusis or high-frequency hearing loss, among carriers of rare variants in MCI candidate genes, particularly PRKRA. The association between PRKRA variants and MCI was independent of APOE ε4 allele and known Parkinson’s disease dementia risk variants. In silico modelling and docking show increased binding affinity between mutant PACT ( PRKRA ) and PKR, suggesting over-activation of the PKR-eIF2α integrated stress response. Functional validation using a PRKRA knockout model identified differentially expressed genes enriched in dementia-related pathways. These findings support PRKRA as a potential driver gene in tinnitus-associated MCI. Clinicaltrial.gov: NCT04663828

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.

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.

Background: RNA sequencing (RNA-seq) is a gold standard technology for studying gene and transcript expression. Different transcripts from the same gene are usually determined by varying combinations of exons within the gene, formed by splicing events. One method of studying differential alternative splicing between groups in short-read RNA-seq experiments is through differential exon usage (DEU) analysis, which uses exon-level read counts along with downstream statistical testing strategies. However, the standard exon counting method does not consider exon-junction information, which may reduce the statistical power in detecting splicing alterations. Results: We present a new workflow for differential splicing analysis, called differential exon-junction usage (DEJU). This DEJU analysis workflow adopts a new feature quantification approach that jointly summarises exon and exon–exon junction reads, which are then integrated into the established Rsubread-edgeR/limma frameworks. We performed comprehensive simulation studies to benchmark the performance of DEJU against existing methods. We also applied DEJU to a mouse mammary gland RNA-seq dataset, revealing biologically meaningful splicing events that could not be detected previously. Conclusions: We demonstrate that incorporating exon–exon junction reads significantly improves the detection of differential splicing events. The proposed DEJU workflow offers increased statistical power and computational efficiency compared to widely used existing approaches, while effectively controlling the false discovery rate.

Meniere disease (MD) is a polygenic condition defined by episodes of vertigo associated with sensorineural hearing loss and tinnitus. Genetic studies in familial MD in East Asian population are limited and the potential MD genes remain to be established in non-Finnish European populations. By exome sequencing and rare variant analysis, we search for existing and novel genes associated with MD in a South Korean cohort of 16 MD individuals with bilateral sensorineural hearing loss. We have found one individual with two rare missense variants in the OTOP2 gene, a new candidate gene for MD and three heterozygous variants in the MYO7A gene, supporting the hypothesis of biallelic inheritance. Protein modelling was conducted on three rare missense variants in OTOP2 to further elucidate functional consequences. The structural and functional implications inferred from these models suggest a likely pathogenic role, providing additional insights into the molecular mechanisms underlying MD.

Motivation: RNA sequencing (RNA-seq) is a gold standard technology for studying gene and transcript expression. Different transcripts from the same gene are usually determined by varying combinations of exons within the gene, formed by splicing events. One method of studying differential alternative splicing between groups in short-read RNA-seq experiments is through differential exon usage (DEU) analyses, which use exon-level read counts along with downstream statistical testing strategies. Popular pipelines for these analyses include Rsubread for read alignment and exon-level count quantification, and edgeR and limma for statistical testing of differential splicing. However, the standard Rsubread::featureCounts count summarization method does not consider exon-junction information, which may reduce the statistical power in differential splicing analyses. Results: A new feature quantification approach is proposed to incorporate both exon and exon-junction reads into the popular Rsubread-edgeR and Rsubread-limma frameworks for detecting differential splicing events. This new Differential Exon-Junction Usage (DEJU) analysis pipeline demonstrates increased statistical power compared to existing popular methods while effectively controlling the false discovery rate. Availability and implementation: Data and code to reproduce the results shown in this article are available from https://github.com/TamPham271299/DEJU .