Rare Variants of Putative Candidate Genes Associated With Sporadic Meniere's Disease in East Asian Population

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.

Novel cell types and developmental lineages revealed by single-cell RNA-seq analysis of the mouse crista ampullaris

“…Gene set enrichment analysis (GSEA 98 ) was performed on fold differences in expression using the fgsea package 99 as described previously 100 for canonical pathways (i.e., KEGG 101 , Reactome 102 , Biocarta 103 and PID 104 ) and transcription factor targets 105 from MSigDB v7.0 106 . Gene lists for vestibular disease and dysfunction were curated by supplementing gene lists from Malacards 107 , OMIM 108 , MSigDB v6.2 106 and the International Mouse Phenotyping Consortium (IMPC) 109 with gene-disease associations from literature 28,[110][111][112][113][114] .…”

Association between Rheumatoid Arthritis and Meniere’s Disease: A Longitudinal Follow-Up Study Using a National Health Screening Cohort

“…The association of RA with MD may be limited to certain types of MD, such as autoimmune-mediated MD. Although autoimmunity is one of the pathophysiologic factors associated with the occurrence of MD [ 10 ], other pathophysiologic factors have been proposed to underlie the occurrence of MD, such as inflammation, viral infection [ 25 ], allergy [ 26 ], and genetic factors [ 11 , 27 ]. For instance, a retrospective study reported a higher prevalence of RA and autoimmune disease in patients with familial MD than in patients with sporadic MD (16.9% vs. 4.5%, p = 0.002) [ 28 ].…”

Case Report: Ménière's Disease-Like Symptoms in 22q11.2 Deletion Syndrome

“…A recent study found that non-coding variants in CRKL were significantly associated with risk for conotruncal heart defects in individuals with 22q11.2DS (12). Many genes have been related to hereditary non-syndromic hearing loss and Ménière's disease (13)(14)(15)(16). It is therefore possible that rare variants in these genes could modify audiovestibular phenotype by interacting with TBX1 in 22q11.2DS.…”