RT Journal Article
SR Electronic
T1 Enrichment of damaging missense variants in genes related with axonal guidance signalling in sporadic Meniere’s disease
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 82
OP 88
DO 10.1136/jmedgenet-2019-106159
VO 57
IS 2
A1 Alvaro Gallego-Martinez
A1 Teresa Requena
A1 Pablo Roman-Naranjo
A1 Patrick May
A1 Jose A Lopez-Escamez
YR 2020
UL http://jmg.bmj.com/content/57/2/82.abstract
AB 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.