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Original article
Enrichment of damaging missense variants in genes related with axonal guidance signalling in sporadic Meniere’s disease
  1. Alvaro Gallego-Martinez1,2,
  2. Teresa Requena1,
  3. Pablo Roman-Naranjo1,
  4. Patrick May2,
  5. Jose A Lopez-Escamez1,3
  1. 1 Otology & Neurotology Group CTS 495, Genomic Medicine Area, Centro de Genomica e Investigación Oncológica, Pfizer-Universidad de Granada-Junta de Andalucía, Granada, Spain
  2. 2 Bioinformatics Core, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-Sur-Alzette, Luxembourg
  3. 3 Department of Otolaryngology, Instituto de Investigación Biosanitaria, ibs.GRANADA, Hospital Universitario Virgen de las Nieves, Granada, Spain
  1. Correspondence to Dr Jose A Lopez-Escamez, Genome medicine area, Centro Pfizer - Universidad de Granada - Junta de Andalucia de Genomica e Investigacion Oncologica, Granada 18016, Spain; antonio.lopezescamez{at}


Introduction Meniere’s disease (MD) is a rare inner ear disorder with a significant genetic contribution defined by a core phenotype: episodic vertigo, sensorineural hearing loss and tinnitus. It has been mostly described in sporadic cases, familial cases being around 10% of the observed individuals. It is associated with an accumulation of endolymph in the inner ear, but the molecular underpinnings remain largely unknown. The main molecular pathways showing higher differentially expressed genes in the supporting cells of the inner ear are related to cochlea-vestibular innervation, cell adhesion and leucocyte extravasation. In this study, our objective is to find a burden of rare variants in genes that interact with the main signalling pathways in supporting cells of the inner ear in patients with sporadic MD.

Methods We designed a targeted-sequencing panel including genes related with the main molecular pathways in supporting cells and sequenced 860 Spanish patients with sporadic MD. Variants with minor allele frequencies <0.1 in the gene panel were compared with three independent reference datasets. Variants were classified as loss of function, missense and synonymous. Missense variants with a combined annotation-dependent depletion score of >20 were classified as damaging missense variants.

Results We have observed a significant burden of damaging missense variants in few key genes, including the NTN4 gene, associated with axon guidance signalling pathways in patients with sporadic MD. We have also identified active subnetworks having an enrichment of rare variants in sporadic MD.

Conclusion The burden of missense variants in the NTN4 gene suggests that axonal guidance signalling could be a novel pathway involved in sporadic MD.

  • target-sequencing panel
  • Meniere’s disease
  • burden analysis
  • Spanish population
  • netrin 4

Statistics from


  • contributors TR and JAL-E conceived the main idea of the work. Sample preparation and protocol were carried out by TR and AG-M. AG-M and PM performed the bioinformatics and statistical analysis. Validations of tested SNV were done by AG-M and PR-N. AG-M and JAL-E took the lead in writing and revising the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript.

  • Funding This study was funded by the Luxembourg National Research Fund INTER/Mobility/17/11772209 Grant and EF-0247-2017 from Andalusian Health Government to JALE.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval The Institutional Review Board approved this study protocol for Clinical Research (MS/2014/02).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information.

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