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：

---

鉴定潜在的家族性复发性良性阵发性位置性眩晕的遗传变异。

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明确。有证据表明，遗传因素在某些特发性BPPV病例中可能起重要作用，特别是在家族性病例中，但尚未鉴定出负责任的遗传变异。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进行了12个家庭的全外显子组测序（包括非翻译区（UTRs））和另外30个具有复发性BPPV的Sanger的Sanger测序，以鉴定导致体重增加的基因变异对BPPV的易感性。五十个非BPPV家庭被纳入为对照。对候选变体进行的计算机和实验分析表明，神经钙粘蛋白基因PCDHGA10（原钙粘蛋白-γA10）中的插入变体rs113784532（导致截短的移码）是非常强的候选物（与样品对照相比，p = 1.80x10-4； p =相对于ExAC数据为5.85x10-19；相对于NHLBI外显子组数据，p = 4.9x10-3）。即使在年轻时，突变蛋白仍会在BPPV样品中形成大的聚集体，并且与没有[平均44.0±14.0（n = 16）岁和54.4±16.1（n = 36）年]的受试者相比，携带该变异株的受影响受试者的病情发作更早。 ，p = 0.054]。在人和小鼠的内耳组织中，PCDHGA10在神经节，毛细胞和前庭过渡上皮中表达。使用小鼠内耳组织的荧光RNA原位杂交表明，表达随年龄增长而增加。总之，