Abstract
Objectives: The cause of Meniere's disease (MD) is unclear but likely involves genetic and environmental factors. The aim of this study was to investigate the genetic basis underlying MD by screening putative candidate genes for MD.Methods: Sixty-eight patients who met the diagnostic criteria for MD of the Barany Society were included. We performed targeted gene sequencing using next generation sequencing (NGS) panel composed of 45 MD-associated genes. We identified the rare variants causing non-synonymous amino acid changes, stop codons, and insertions/deletions in the coding regions, and excluded the common variants with minor allele frequency >0.01 in public databases. The pathogenicity of the identified variants was analyzed by various predictive tools and protein structural modeling.Results: The average read depth for the targeted regions was 1446.3-fold, and 99.4% of the targeted regions were covered by 20 or more reads, achieving the high quality of the sequencing. After variant filtering, annotation, and interpretation, we identified a total of 15 rare heterozygous variants in 12 (17.6%) sporadic patients. Among them, four variants were detected in familial MD genes (DTNA, FAM136A, DPT), and the remaining 11 in MD-associated genes (PTPN22, NFKB1, CXCL10, TLR2, MTHFR, SLC44A2, NOS3, NOTCH2). Three patients had the variants in two or more genes. All variants were not detected in our healthy controls (n = 100). No significant differences were observed between patients with and without a genetic variant in terms of sex, mean age of onset, bilaterality, the type of MD, and hearing threshold at diagnosis.Conclusions: Our study identified rare variants of putative candidate genes in some of MD patients. The genes were related to the formation of inner ear structures, the immune-associated process, or systemic hemostasis derangement, suggesting the multiple genetic predispositions in the development of MD.
Highlights
Meniere’s disease (MD) is a clinical syndrome that consists of episodes of spontaneous vertigo usually associated with unilateral fluctuating sensorineural hearing loss (SNHL), tinnitus and aural fullness [1]
Recent studies using whole-exome sequencing (WES) for Spanish families with MD have identified probably pathogenic rare variants in candidate genes including FAM136A, DTNA, PRKCB, DPT, and SEMA3D [36,37,38]. Since these genes encode proteins that may be relevant to the formation or maintaining of inner ear structures, the identified rare variants are expected to account for the genetic contribution of MD, but further replicative studies in distinct populations are needed
Annotation, and interpretation, we identified a total of 15 rare heterozygous variants in 12 (17.6%) sporadic patients (Table 1)
Summary
Meniere’s disease (MD) is a clinical syndrome that consists of episodes of spontaneous vertigo usually associated with unilateral fluctuating sensorineural hearing loss (SNHL), tinnitus and aural fullness [1]. Recent studies using whole-exome sequencing (WES) for Spanish families with MD have identified probably pathogenic rare variants in candidate genes including FAM136A, DTNA, PRKCB, DPT, and SEMA3D [36,37,38]. Since these genes encode proteins that may be relevant to the formation or maintaining of inner ear structures, the identified rare variants are expected to account for the genetic contribution of MD, but further replicative studies in distinct populations are needed.
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