PDF(Pubmed)
Abstract：
BACKGROUND: Ménière\'s disease (MD) is a disorder of the inner ear that causes episodic bouts of severe dizziness, roaring tinnitus, and fluctuating hearing loss. To date, no targeted therapy exists. As such, we have undertaken a large whole genome sequencing study on carefully phenotyped unilateral MD patients with the goal of gene/pathway discovery and a move towards targeted intervention. This study was a retrospective review of patients with a history of Ménière\'s disease. Genomic DNA, acquired from saliva samples, was purified and subjected to whole genome sequencing.
RESULTS: Stringent variant calling, performed on 511 samples passing quality checks, followed by gene-based filtering by recurrence and proximity in molecular interaction networks, led to 481 high priority MD genes. These high priority genes, including MPHOSPH8, MYO18A, TRIOBP, OTOGL, TNC, and MYO6, were previously implicated in hearing loss, balance, and cochlear function, and were significantly enriched in common variant studies of hearing loss. Validation in an independent MD cohort confirmed 82 recurrent genes. Pathway analysis pointed to cell-cell adhesion, extracellular matrix, and cellular energy maintenance as key mediators of MD. Furthermore, the MD-prioritized genes were highly expressed in human inner ear hair cells and dark/vestibular cells, and were differentially expressed in a mouse model of hearing loss.
CONCLUSIONS: By enabling the development of model systems that may lead to targeted therapies and MD screening panels, the genes and variants identified in this study will inform diagnosis and treatment of MD.
RESULTS: Stringent variant calling, performed on 511 samples passing quality checks, followed by gene-based filtering by recurrence and proximity in molecular interaction networks, led to 481 high priority MD genes. These high priority genes, including MPHOSPH8, MYO18A, TRIOBP, OTOGL, TNC, and MYO6, were previously implicated in hearing loss, balance, and cochlear function, and were significantly enriched in common variant studies of hearing loss. Validation in an independent MD cohort confirmed 82 recurrent genes. Pathway analysis pointed to cell-cell adhesion, extracellular matrix, and cellular energy maintenance as key mediators of MD. Furthermore, the MD-prioritized genes were highly expressed in human inner ear hair cells and dark/vestibular cells, and were differentially expressed in a mouse model of hearing loss.
CONCLUSIONS: By enabling the development of model systems that may lead to targeted therapies and MD screening panels, the genes and variants identified in this study will inform diagnosis and treatment of MD.
摘要：
背景：梅尼埃病（MD）是一种内耳疾病，可引起严重头晕的发作性发作，咆哮的耳鸣，和波动性听力损失。迄今为止,没有靶向治疗。因此，我们对经过仔细分型的单侧MD患者进行了一项大型全基因组测序研究,目的是发现基因/通路,并朝着有针对性的干预方向迈进.这项研究是对有梅尼埃病病史的患者的回顾性研究。基因组DNA,从唾液样本中获得，纯化并进行全基因组测序。
结果：严格的变异呼叫，对通过质量检查的511个样品进行了检查，然后是基于基因的过滤，在分子相互作用网络中进行复发和接近，导致481个高优先级MD基因。这些高度优先的基因，包括MPHOSPH8，MYO18A，TRIOBP,OTOGL,TNC,和MYO6，以前与听力损失有关，balance,和耳蜗功能，并显著丰富了常见的听力损失变异研究。在一个独立的MD队列中的验证证实了82个复发基因。路径分析指出细胞-细胞粘附，细胞外基质，和细胞能量维持作为MD的关键介体。此外，MD优先基因在人内耳毛细胞和暗/前庭细胞中高表达，并在听力损失小鼠模型中差异表达。
结论：通过开发可能导致靶向治疗和MD筛查小组的模型系统，本研究中确定的基因和变异将为MD的诊断和治疗提供信息.
结果：严格的变异呼叫，对通过质量检查的511个样品进行了检查，然后是基于基因的过滤，在分子相互作用网络中进行复发和接近，导致481个高优先级MD基因。这些高度优先的基因，包括MPHOSPH8，MYO18A，TRIOBP,OTOGL,TNC,和MYO6，以前与听力损失有关，balance,和耳蜗功能，并显著丰富了常见的听力损失变异研究。在一个独立的MD队列中的验证证实了82个复发基因。路径分析指出细胞-细胞粘附，细胞外基质，和细胞能量维持作为MD的关键介体。此外，MD优先基因在人内耳毛细胞和暗/前庭细胞中高表达，并在听力损失小鼠模型中差异表达。
结论：通过开发可能导致靶向治疗和MD筛查小组的模型系统，本研究中确定的基因和变异将为MD的诊断和治疗提供信息.
