Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo in humans, yet the molecular etiology is currently unknown. Evidence suggests that genetic factors may play an important role in some cases of idiopathic BPPV, particularly in familial cases, but the responsible genetic variants have not been identified. In this study, we performed whole exome sequencing [including untranslated regions (UTRs)] of 12 families and Sanger sequencing of additional 30 families with recurrent BPPV in Caucasians from the United States (US) Midwest region, to identify the genetic variants responsible for heightened susceptibility to BPPV. Fifty non-BPPV families were included as controls. In silico and experimental analyses of candidate variants show that an insertion variant rs113784532 (frameshift causing truncation) in the neural cadherin gene PCDHGA10 (protocadherin-gamma A10) is an exceedingly strong candidate (p = 1.80x10-4 vs. sample controls; p = 5.85x10-19 vs. ExAC data; p = 4.9x10-3 vs. NHLBI exome data). The mutant protein forms large aggregates in BPPV samples even at young ages, and affected subjects carrying this variant have an earlier onset of the condition than those without [average 44.0±14.0 (n = 16) versus 54.4±16.1 (n = 36) years old, p = 0.054]. In both human and mouse inner ear tissues, PCDHGA10 is expressed in ganglia, hair cells and vestibular transitional epithelia. Fluorescent RNA in situ hybridization using mouse inner ear tissues shows that expression increases with age. In summary, our data show that a variant in the PCDHGA10 gene may be involved in causing or aggravating some familial cases of recurrent idiopathic BPPV.

中文翻译：

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遗传变异的识别潜在的家族性复发性良性阵发性位置性眩晕病例。

良性阵发性位置性眩晕 (BPPV) 是人类眩晕的最常见原因，但分子病因目前尚不清楚。有证据表明，遗传因素可能在某些特发性 BPPV 病例中发挥重要作用，尤其是在家族性病例中，但尚未确定相关的遗传变异。在这项研究中，我们对来自美国（美国）中西部地区的高加索人的 12 个家庭进行了全外显子组测序 [包括非翻译区 (UTR)]，并对另外 30 个患有复发性 BPPV 的家庭进行了 Sanger 测序，以确定导致对 BPPV 的易感性。包括 50 个非 BPPV 家庭作为对照。候选变体的计算机模拟和实验分析表明，神经钙粘蛋白基因 PCDHGA10（原钙粘蛋白-γA10）中的插入变体 rs113784532（移码导致截断）是一个非常强大的候选者（p = 1.80x10-4 与样本对照；p = 5.85x10-19 对比 ExAC 数据；p = 4.9x10-3 对比 NHLBI 外显子组数据）。即使在年轻的时候，突变蛋白在 BPPV 样本中也会形成大的聚集体，并且携带这种变异的受影响受试者比没有 [平均 44.0±14.0 (n = 16) 年与 54.4±16.1 (n = 36) 年的受试者更早发病旧，p = 0.054]。在人和小鼠的内耳组织中，PCDHGA10 在神经节、毛细胞和前庭移行上皮细胞中表达。使用小鼠内耳组织的荧光 RNA 原位杂交显示表达随着年龄的增长而增加。总之，