Ski-slope hearing loss (HL), which refers to increased auditory threshold at high frequencies, is common in adults. However, genetic contributions to this post-lingual HL remain largely unknown. Here, we prospectively investigated deafness-associated and novel candidate genes causing ski-slope HL. We analyzed 192 families with post-lingual HL via gene panel and/or exome sequencing. With an overall molecular diagnostic rate of 35.4% (68/192) in post-lingual HL, ski-slope HL showed a lower diagnostic rate (30.7%) compared with other conditions (40.7%). In patients who showed HL onset before the age of 40, genetic diagnostic probability was significantly lower for ski-slope HL than for other conditions. Further analysis of 51 genetically undiagnosed patients in the ski-slope HL group identified three variants in delta-like ligand 1 (DLL1), a Notch ligand, which presented in vitro gain-of-function effects on Notch downstream signaling. In conclusion, genetic diagnostic rates in post-lingual HL varied according to audiogram patterns with age-of-onset as a confounding factor. DLL1 was identified as a candidate gene causing ski-slope HL.

滑雪坡听力损失 (HL) 是指高频听觉阈值增加，在成人中很常见。然而，这种语言后 HL 的遗传贡献在很大程度上仍然未知。在这里，我们前瞻性地研究了导致滑雪坡 HL 的耳聋相关和新的候选基因。我们通过基因面板和/或外显子组测序分析了 192 个语后 HL 家族。舌后 HL 的总体分子诊断率为 35.4% (68/192)，与其他条件 (40.7%) 相比，滑雪坡 HL 的诊断率 (30.7%) 较低。在 40 岁之前出现 HL 发病的患者中，滑雪坡 HL 的遗传诊断概率显着低于其他情况。对滑雪坡 HL 组中 51 名遗传未确诊患者的进一步分析确定了 delta 样配体 1 的三个变体。DLL1 )，一种 Notch 配体，在体外对 Notch 下游信号传导产生功能增益效应。总之，语后 HL 的遗传诊断率因听力图模式而异，发病年龄是一个混杂因素。DLL1被确定为导致滑雪坡 HL 的候选基因。