Otology & Neurotology Group CTS 495, Department of Genomic Medicine, Centro Pfizer-Universidad de Granada-Junta de Andalucía de Genómica e Investigación Oncológica, Granada, Spain.
Division of Otoneurology, Department of Otorhinolaryngology, Complexo Hospitalario Universitario, Santiago de Compostela, Spain.
Ear Hear. 2020 Nov/Dec;41(6):1598-1605. doi: 10.1097/AUD.0000000000000878.
Meniere's disease (MD) is a rare inner ear disorder characterized by sensorineural hearing loss, episodic vertigo, and tinnitus. Familial MD has been reported in 6 to 9% of sporadic cases, and few genes including FAM136A, DTNA, PRKCB, SEMA3D, and DPT have been involved in single families, suggesting genetic heterogeneity. In this study, the authors recruited 46 families with MD to search for relevant candidate genes for hearing loss in familial MD.
Exome sequencing data from MD patients were analyzed to search for rare variants in hearing loss genes in a case-control study. A total of 109 patients with MD (73 familial cases and 36 early-onset sporadic patients) diagnosed according to the diagnostic criteria defined by the Barany Society were recruited in 11 hospitals. The allelic frequencies of rare variants in hearing loss genes were calculated in individuals with familial MD. A single rare variant analysis and a gene burden analysis (GBA) were conducted in the dataset selecting 1 patient from each family. Allelic frequencies from European and Spanish reference datasets were used as controls.
A total of 5136 single-nucleotide variants in hearing loss genes were considered for single rare variant analysis in familial MD cases, but only 1 heterozygous likely pathogenic variant in the OTOG gene (rs552304627) was found in 2 unrelated families. The gene burden analysis found an enrichment of rare missense variants in the OTOG gene in familial MD. So, 15 of 46 families (33%) showed at least 1 rare missense variant in the OTOG gene, suggesting a key role in familial MD.
The authors found an enrichment of multiplex rare missense variants in the OTOG gene in familial MD. This finding supports OTOG as a relevant gene in familial MD and set the groundwork for genetic testing in MD.
梅尼埃病（MD）是一种罕见的内耳疾病，其特征为感觉神经性听力损失、阵发性眩晕和耳鸣。家族性 MD 已在 6%至 9%的散发性病例中报道，少数基因，包括 FAM136A、DTNA、PRKCB、SEMA3D 和 DPT，已涉及单个家族，提示存在遗传异质性。在这项研究中，作者招募了 46 个 MD 家族，以寻找家族性 MD 中听力损失相关的候选基因。
对 MD 患者的外显子组测序数据进行分析，以在病例对照研究中寻找听力损失基因中的罕见变异。共招募了 11 家医院的 109 名 MD 患者（73 例家族性病例和 36 例早发性散发性病例），根据 Barany 学会定义的诊断标准进行诊断。计算了家族性 MD 个体中听力损失基因罕见变异的等位基因频率。在从每个家族中选择 1 名患者的数据集上进行了单一罕见变异分析和基因负担分析（GBA）。使用欧洲和西班牙参考数据集的等位基因频率作为对照。
在家族性 MD 病例中进行单一罕见变异分析时考虑了 5136 个听力损失基因的单核苷酸变异，但仅在 2 个无关家族中发现了 OTOG 基因（rs552304627）中的 1 个杂合的可能致病性变异。基因负担分析发现，OTOG 基因中的罕见错义变异在家族性 MD 中富集。因此，46 个家族中有 15 个（33%）家族至少在 OTOG 基因中存在 1 个罕见错义变异，提示 OTOG 在家族性 MD 中起关键作用。
作者发现 OTOG 基因中存在大量罕见的错义变异在家族性 MD 中富集。这一发现支持 OTOG 是家族性 MD 中的一个相关基因，并为 MD 的基因检测奠定了基础。
