遗传性耳聋分子诊断及梯级检测策略应用

doi:10.16288/j.yczz.22-206

遗传 ›› 2023, Vol. 45 ›› Issue (1): 29-41.doi: 10.16288/j.yczz.22-206

遗传性耳聋分子诊断及梯级检测策略应用

曾焙枰¹(), 许红恩²(), 毛璐², 汤文学³()

1.郑州大学华大基因学院与医药科学研究院，郑州 450052
2.郑州大学医学科学院精准医学中心，郑州 450052
3.郑州大学第二附属医院精准医学研究应用中心，郑州 450014

收稿日期:2022-09-22 修回日期:2022-10-29 出版日期:2023-01-20 发布日期:2022-11-04
通讯作者: 汤文学 E-mail:beipingzeng1120@163.com;beipingzeng1120@163.com;hongen_xu@zzu.edu.cn;hongen_xu@zzu.edu.cn;twx@zzu.edu.cn
作者简介:曾焙枰，硕士研究生，专业方向：遗传性耳聋分子诊断。E-mail: beipingzeng1120@163.com|许红恩，博士，讲师，研究方向：遗传性耳聋与肾病。E-mail: hongen_xu@zzu.edu.cn;
曾焙枰和许红恩并列第一作者。
基金资助:
郑州市协同创新项目(18XTZX12004);河南省医学科技攻关计划联合共建项目(LHGJ20190317)

Molecular diagnosis of hereditary deafness and application of stepwise testing strategy

Beiping Zeng¹(), Hongen Xu²(), Lu Mao², Wenxue Tang³()

1. BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
2. Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou 450052, China
3. The Research and Application Center of Precision Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China

Received:2022-09-22 Revised:2022-10-29 Online:2023-01-20 Published:2022-11-04
Contact: Tang Wenxue E-mail:beipingzeng1120@163.com;beipingzeng1120@163.com;hongen_xu@zzu.edu.cn;hongen_xu@zzu.edu.cn;twx@zzu.edu.cn
Supported by:
Supported by the Collaborative Innovation Project of Zhengzhou No(18XTZX12004);the Joint Project of Medical Science and Technology Research in Henan Province No(LHGJ20190317)

摘要/Abstract

摘要：

遗传性耳聋是人类最常见的感觉障碍之一，具有高度遗传异质性。目前常用的遗传性耳聋分子诊断方法包括基因芯片、Sanger测序、靶向富集测序和全外显子组测序等，诊断率可达33.5%~56.67%，但还有相当一部分患者不能进行及时有效的分子病因诊断。考虑到患者家庭的经济负担及目前全外显子组/全基因组测序仍相对昂贵，根据患者情况提供包含多种检测手段的梯级诊断策略至关重要。因此，本文对遗传性耳聋分子诊断现状以及梯级检测在遗传性耳聋分子诊断中的应用进行综述，以期为诊断策略的选择提供参考。

关键词: 遗传性耳聋, 遗传异质性, 分子诊断, 高通量检测, 梯级检测

Abstract:

Hereditary deafness is one of the most common sensory disorders in humans, and exhibits high genetic heterogeneity. At present, the commonly used molecular diagnostic methods include gene chip, Sanger sequencing, targeted enrichment sequencing, and whole-exome sequencing, with diagnosis rates reaching 33.5%-56.67%. However, there are still a considerable number of patients who can not get a timely and definitive molecular diagnosis. Furthermore, considering the economic burden on patients’ families and the relatively high cost of whole-exome or whole-genome sequencing, it is vital to provide stepwise strategies combining multiple detection methods according to the phenotypes of patients. In this review, we evaluate and discuss the utility of molecular diagnosis and the application of stepwise testing strategies in hereditary deafness to provide reference for the selection of diagnostic strategies.

Key words: hereditary deafness, genetic heterogeneity, molecular diagnosis, high-throughput screening, stepwise testing strategy

曾焙枰, 许红恩, 毛璐, 汤文学. 遗传性耳聋分子诊断及梯级检测策略应用[J]. 遗传, 2023, 45(1): 29-41.

Beiping Zeng, Hongen Xu, Lu Mao, Wenxue Tang. Molecular diagnosis of hereditary deafness and application of stepwise testing strategy[J]. Hereditas(Beijing), 2023, 45(1): 29-41.

图/表 3

图1

表1

高通量检测技术在遗传性耳聋分子诊断中的应用"

技术	代表性研究	主要进展	优点	局限性
基因芯片	Li等^[54]，2007	首次利用基因芯片检测	自动化、微型性，是进行耳聋基因分子诊断最快捷的方法之一	只涵盖4个耳聋基因的热点突变，携带罕见突变的患者不能得到明确诊断
	He等^[13]，2017	在2500个新生儿中，检测到101名(4.04%)为阳性
	Dai等^[12]，2019	在180 469名新生儿中，检测到8136名(4.508%)为阳性
耳聋基因靶向富集测序	Smith等^[58]，2010	首次发表了耳聋基因靶向富集测序对听力损失患者进行分子诊断的研究	低成本、个性化、易解释，在各大研究机构和公司广泛应用	随着耳聋新基因的发现，基因panel需要持续更新；基因panel通常无法涵盖内含子区域及基因调控区域的突变
	Tang等^[59]，2012	提出了一种基于cDNA探针捕获已知耳聋基因外显子，并进行高通量测序从而实现耳聋分子诊断的方法
	Sloan-Heggen等^[37]，2016	1119名听力损失患者，诊断率为39%
	Cabanillas等^[60]，2018	50名听力损失患者，诊断率为42%
	Yuan等^[25]，2020	433名耳聋患者，诊断率为52.19%
全外显子组测序	Zazo Seco等^[40]，2017	200名耳聋患者，诊断率为33.5%	较全基因组测序更经济高效；能获得编码区测序覆盖度更深、准确性更高的数据；可获得与表型相关的大部分遗传变异	鉴定内含子或基因调控区域突变的能力不足；检出结构重排、CNV和串联重复等变异的能力有所欠缺
	Sheppard等^[45]，2018	43例听力损失儿童患者，诊断率为37.2%
	Feng等^[46]，2019	33个听力损失家系，诊断率为48.5%
	Downie等^[42]，2020	106名中度至重度听力损失婴儿，诊断率为56%
全基因组测序	Vuckovic等^[70]，2018	确定了21个与年龄性听力损失相关的基因	检测全面，能够识别非编码区域中的变异，可分析结构变异；无目标基因捕获步骤，上机测序更快速便捷	成本昂贵；数据分析和变异解读存在一定挑战，比如与同源基因相关的轻中度遗传性耳聋的变异分析(STRC基因)
全基因组测序	Le Nabec等^[71]，2021	在9名携带GJB2单杂合突变的DFNB1患者中，发现4名患者携带GJB2的另一个变异	检测全面，能够识别非编码区域中的变异，可分析结构变异；无目标基因捕获步骤，上机测序更快速便捷	成本昂贵；数据分析和变异解读存在一定挑战，比如与同源基因相关的轻中度遗传性耳聋的变异分析(STRC基因)
三代测序	Dai等^[85]，2021	在3名未诊断的内耳畸形(IP-III)患者中，发现2名患者携带POU3F4基因的结构变异	真正实现了单分子测序；超长的测序读长，利于分析结构变异；可直接检测碱基修饰；可应用于转录组研究	精确度较低，测序深度有限；成本昂贵，还达不到广泛应用的条件

表1

图2

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遗传性耳聋分子诊断及梯级检测策略应用

Molecular diagnosis of hereditary deafness and application of stepwise testing strategy

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