Background Hearing loss is one of the most common birth disorders in humans with an estimated prevalence of 1-3 in every 1000 newborns. This study has investigated the molecular etiology of a deaf cohort using a stepwise strategy to effectively diagnose patients and the challenges faced to verify genetic heterogenicity and the variable mutation spectrums of hearing loss. Methods In order to target known pathogenic variants, multiplex PCR plus next-generation sequencing was applied in the first tier, while undiagnosed cases were further referred to exome sequencing. A total of 92 unrelated patients with nonsyndromic hearing loss were enrolled. Results In total, 64% (59/92) of patients were molecularly diagnosed, 44 of which were identified in the first tier by multiplex PCR plus sequencing. Of 48 undiagnosed patients from the first tier, exome sequencing identified eleven diagnoses (23%, 11/48) and four probably diagnoses (8%, 4/48). The rate of secondary findings of exome sequencing in our cohort is 3.4%. Conclusion The research presented a molecular diagnosis spectrum of 92 non-syndromic hearing loss patients and demonstrated the benefits of using the stepwise diagnostic approach in the genetic test of the non-syndromic hearing loss patient cohort.

中文翻译：

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使用逐步方法对非综合征性听力损失患者进行分子诊断

背景听力损失是人类最常见的出生疾病之一，估计每1000名新生儿中有1-3名患病。这项研究使用逐步策略来有效诊断患者，并验证遗传异质性和听力损失的可变突变谱，从而研究了聋人的分子病因。方法为了靶向已知的病原体变体，在第一层应用了多重PCR和下一代测序，而未确诊的病例进一步称为外显子组测序。总共纳入了92例非综合征性听力损失的无关患者。结果总共有64％（59/92）的患者被分子诊断，其中44例通过多重PCR加测序在第一级中被鉴定。在第一级的48位未诊断患者中，外显子组测序确定了11个诊断（23％，11/48）和4个可能的诊断（8％，4/48）。在我们的队列中，外显子组测序的次要发现率为3.4％。结论该研究提出了92例非综合征性听力损失患者的分子诊断谱，并证明了在非综合征性听力损失患者队列的基因测试中使用逐步诊断方法的益处。