Wang Wenjia, Li Jin, Lan Lan, Xie Linyi, Xiong Fen, Guan Jing, Wang Hongyang, Wang Qiuju
College of Otolaryngology, Head and Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
National Clinical Research Center for Otolaryngologic Diseases, Beijing, China.
Front Cell Dev Biol. 2021 Oct 8;9:749484. doi: 10.3389/fcell.2021.749484. eCollection 2021.
The objective of this study is to analyze the genotype-phenotype correlation of patients with auditory neuropathy (AN), which is a clinical condition featuring normal cochlear responses and abnormal neural responses, and c.2452 G > A (p.E818K), which has been generally recognized as a genetic cause of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. Four patients diagnosed as AN by clinical evaluation and otoacoustic emission and auditory brainstem responses were recruited and analyzed by next-generation sequencing to identify candidate disease-causing variants. Sanger sequencing was performed on the patients and their parents to verify the results, and short tandem repeat-based testing was conducted to confirm the biological relationship between the parents and the patients. Furthermore, cochlear implantation (CI) was performed in one AN patient to reconstruct hearing. Four subjects with AN were identified to share a variant, p.E818K in the gene. Except for the AN phenotype, patients 1 and 2 exhibited varying degrees of neurological symptoms, implying that they can be diagnosed as CAPOS syndrome. During the 15 years follow-up of patient 1, we observed delayed neurological events and progressive bilateral sensorineural hearing loss in pure tone threshold (pure tone audiometry, PTA). Patient 2 underwent CI on his left ear, and the result was poor. The other two patients (patient 3 and patient 4, who were 8 and 6 years old, respectively) denied any neurological symptoms. p.E818K has rarely been documented in the Chinese AN population. Our study confirms that p.E818K in the gene is a multiethnic cause of AN in Chinese individuals. Our study further demonstrates the significance of genetic testing for this specific mutation for identifying the special subtype of AN with somewhat favorable CI outcome and offers a more accurate genetic counseling about the specific mutation.
本研究的目的是分析听神经病（AN）患者的基因型-表型相关性。听神经病是一种临床病症，其特征为耳蜗反应正常而神经反应异常，以及c.2452 G > A（p.E818K），该突变已被普遍认为是小脑共济失调、无反射、高弓足、视神经萎缩和感音神经性听力损失（CAPOS）综合征的遗传病因。招募了4例经临床评估、耳声发射和听性脑干反应诊断为AN的患者，并通过下一代测序进行分析，以鉴定候选致病变异。对患者及其父母进行桑格测序以验证结果，并进行基于短串联重复序列的检测以确认父母与患者之间的生物学关系。此外，对1例AN患者进行了人工耳蜗植入（CI）以重建听力。4例AN受试者被鉴定在该基因中共享一个p.E818K变异。除AN表型外，患者1和患者2表现出不同程度的神经症状，这意味着他们可被诊断为CAPOS综合征。在对患者1的15年随访中，我们观察到神经事件延迟以及纯音阈值（纯音听力测定，PTA）出现进行性双侧感音神经性听力损失。患者2左耳接受了CI，结果不佳。另外两名患者（患者3和患者4，分别为8岁和6岁）否认有任何神经症状。p.E818K在中国AN人群中鲜有报道。我们的研究证实该基因中的p.E818K是中国个体AN的多民族病因。我们的研究进一步证明了针对这一特定突变进行基因检测对于识别具有一定良好CI结果的AN特殊亚型的重要性，并为该特定突变提供了更准确 的遗传咨询。
