Familial Temperature-Sensitive Auditory Neuropathy: Distinctive Clinical Courses Caused by Variants of the OTOF Gene.
Familial Temperature-Sensitive Auditory Neuropathy: Distinctive Clinical Courses Caused by Variants of the OTOF Gene.
复制标题
家族性温度敏感性听觉神经病：由 OTOF 基因变异引起的独特临床过程
DOI：
10.3389/fcell.2021.732930
复制
发表时间：
2021
影响因子：
5.5
通讯作者：
Li XP
中科院分区：
文献类型：
--
作者：
Zhu YM;Li Q;Gao X;Li YF;Liu YL;Dai P;Li XP
目的：研究家族性温度敏感型听神经病(TSAN)的临床病程和遗传病因学。TSAN是听神经病(AN)的一种非常罕见的亚型，其核心体温升高导致听力阈值升高，并评估一个TSAN家系的基因-表型相关性。方法：本研究纳入了一个非血缘关系的中国家庭的6名成员，其中包括4名兄弟姐妹，他们在发烧时抱怨交流困难。在发热期和无热期对这四个兄弟姐妹的临床和听力特征进行了全面的评估，并利用下一代测序(NGS)技术探索了听力损失(HL)的遗传病因。他们的父母没有抱怨由于体温变化而引起的HL波动，只参加了遗传学部分的研究。结果：发热期听力学检查符合AN的经典诊断标准，包括轻度HL、言语辨别力差、耳蜗微音素(CMS)保留和听性脑干反应(ABR)缺失。重要的是，与以前报道的TSAN病例不同，我们的患者的ABR和耳蜗电(ECochG)信号在无热期改善到正常。遗传分析证实了OTOF基因(编码Otoferlin蛋白)的一个复合杂合型变异体，包括一个已报道的致病变异体c.5098G>；C(p.Glu1700Gln)和一个新变异体c.4882C>；A(p.Pro1628Thr)。这两个已鉴定的突变体都没有影响与耳铁蛋白主要功能相关的C2结构域。这两个变异体在该家系中都忠实地与Tsan共分离，表明OTOF是该家系常染色体隐性性状分离的致病基因。结论：ABR缺失(或明显异常)的CMS是诊断AN的可靠指标。TSAN中神经递质释放功能障碍引起的表型的严重程度可能反映了改变Otoferlin C2结构域的变异。本研究的观察结果丰富了目前对TSAN表型和基因的认识，为进一步研究其发病机制奠定了基础。
Objective: To investigate the clinical course and genetic etiology of familial temperature-sensitive auditory neuropathy (TSAN), which is a very rare subtype of auditory neuropathy (AN) that involves an elevation of hearing thresholds due to an increase in the core body temperature, and to evaluate the genotype–phenotype correlations in a family with TSAN. Methods: Six members of a non-consanguineous Chinese family, including four siblings complaining of communication difficulties when febrile, were enrolled in this study. The clinical and audiological profiles of the four siblings were fully evaluated during both febrile and afebrile episodes, and the genetic etiology of hearing loss (HL) was explored using next-generation sequencing (NGS) technology. Their parents, who had no complaints of fluctuating HL due to body temperature variation, were enrolled for the genetics portion only. Results: Audiological tests during the patients’ febrile episodes met the classical diagnostic criteria for AN, including mild HL, poor speech discrimination, preserved cochlear microphonics (CMs), and absent auditory brainstem responses (ABRs). Importantly, unlike the pattern observed in previously reported cases of TSAN, the ABRs and electrocochleography (ECochG) signals of our patients improved to normal during afebrile periods. Genetic analysis identified a compound heterozygous variant of the OTOF gene (which encodes the otoferlin protein), including one previously reported pathogenic variant, c.5098G > C (p.Glu1700Gln), and one novel variant, c.4882C > A (p.Pro1628Thr). Neither of the identified variants affected the C2 domains related to the main function of otoferlin. Both variants faithfully cosegregated with TSAN within the pedigree, suggesting that OTOF is the causative gene of the autosomal recessive trait segregation in this family. Conclusion: The presence of CMs with absent (or markedly abnormal) ABRs is a reliable criterion for diagnosing AN. The severity of the phenotype caused by dysfunctional neurotransmitter release in TSAN may reflect variants that alter the C2 domains of otoferlin. The observations from this study enrich the current understanding of the phenotype and genotype of TSAN and may lay a foundation for further research on its pathogenesis.
登录
查看更多内容
DOI：
10.1038/gim.2017.143
发表时间：
2018-04
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Almontashiri NAM;Alswaid A;Oza A;Al-Mazrou KA;Elrehim O;Tayoun AA;Rehm HL;Amr SS
通讯作者：
Amr SS
影响因子：
5.3
作者：
Fu X;Wan P;Li P;Wang J;Guo S;Zhang Y;An Y;Ye C;Liu Z;Gao J;Yang J;Fan J;Chai R
通讯作者：
Chai R
DOI：
10.1007/s12070-018-1494-1
发表时间：
2019-03-01
影响因子：
0.6
作者：
Gohari, Nasrin;Emami, Seyede Farank;Borzuei, Mahta
通讯作者：
Borzuei, Mahta
DOI：
10.1016/j.jacr.2018.09.020
发表时间：
2018-11-01
期刊：
Journal of the American College of Radiology : JACR
影响因子：
--
作者：
Sharma, Aseem;Kirsch, Claudia F E;Bykowski, Julie
通讯作者：
Bykowski, Julie
影响因子：
5.1
作者：
Fu, Xiaolong;An, Yachun;Chai, Renjie
通讯作者：
Chai, Renjie