Otology & Neurotology Group CTS 495, Genomic Medicine Area, Centro de Genomica e Investigación Oncológica, Pfizer-Universidad de Granada-Junta de Andalucía, Granada, Spain.
Bioinformatics Core, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-Sur-Alzette, Luxembourg.
J Med Genet. 2020 Feb;57(2):82-88. doi: 10.1136/jmedgenet-2019-106159. Epub 2019 Sep 7.
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.
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.
We have observed a significant burden of damaging missense variants in few key genes, including the 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.
The burden of missense variants in the gene suggests that axonal guidance signalling could be a novel pathway involved in sporadic MD.
梅尼埃病（MD）是一种罕见的内耳疾病，具有显著的遗传贡献，其核心表型为阵发性眩晕、感音神经性听力损失和耳鸣。它主要在散发病例中描述，家族病例约占观察到的个体的 10%。它与内耳内淋巴液的积累有关，但分子基础仍知之甚少。在内耳支持细胞中显示更高差异表达基因的主要分子途径与耳蜗-前庭神经支配、细胞黏附和白细胞渗出有关。在这项研究中，我们的目标是在患有散发性 MD 的患者中发现与内耳支持细胞主要信号通路相互作用的基因中罕见变异的负担。
我们设计了一个靶向测序面板，包括与内耳支持细胞主要分子途径相关的基因，并对 860 名西班牙散发性 MD 患者进行了测序。与基因面板中次要等位基因频率<0.1 的变异与三个独立的参考数据集进行了比较。将变异分类为功能丧失、错义和同义。综合注释依赖耗竭评分>20 的错义变异被归类为有害错义变异。
我们观察到少数关键基因中存在显著的有害错义变异负担，包括 基因，该基因与散发性 MD 患者的轴突导向信号通路有关。我们还鉴定了具有散发性 MD 中罕见变异富集的活跃子网络。
基因中错义变异的负担表明，轴突导向信号可能是参与散发性 MD 的新途径。
