Department of Genetics, World Hearing Center, Institute of Physiology and Pathology of Hearing, M. Mochnackiego 10, 02-042, Warsaw, Poland.
Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
J Transl Med. 2019 Aug 14;17(1):269. doi: 10.1186/s12967-019-2018-9.
Hearing loss (HL) is the most common disability of human senses characterized by a great allelic heterogeneity. GJB2 and TMPRSS3 are two well-known HL genes typically underlying its monogenic form. Recently, TMPRSS3/GJB2 digenic inheritance has been proposed. As results of genetic testing can be easily overinterpreted, we aimed to verify the hypothesis.
From genetic database of HL patients with at least one TMPRSS3 pathogenic variants we have selected individuals with additional GJB2 pathogenic variants. All of the available family members were recruited for the study. Segregation analysis of the respective TMPRSS3 and GJB2 pathogenic variants was performed within the families.
The strategy has allowed to identify four individuals who were double heterozygous for known pathogenic TMPRSS3 and GJB2 variants. Two individuals from different families had GJB2 c.35delG and TMPRSS3 c.208delC and in two other individuals from one family GJB2 c.35delG together with TMPRSS3 c.1343T>C variants were found. None of these subjects has ever reported hearing problems and their hearing status was normal.
Our data provide evidence against TMPRSS3/GJB2 digenic inheritance of HL. As high throughput sequencing is increasingly used for genetic testing, particular caution should be taken to provide the patients with accurate genetic counseling.
听力损失（HL）是人类感官最常见的残疾，其具有很大的等位基因异质性。GJB2 和 TMPRSS3 是两种众所周知的 HL 基因，通常是其单基因形式的基础。最近，已经提出了 TMPRSS3/GJB2 双基因遗传。由于遗传检测的结果很容易被过度解释，我们旨在验证这一假设。
从至少有一种 TMPRSS3 致病性变异的 HL 患者的遗传数据库中，我们选择了具有额外 GJB2 致病性变异的个体。所有可用的家庭成员都被招募参加了这项研究。在家庭内对各自的 TMPRSS3 和 GJB2 致病性变异进行了分离分析。
该策略允许我们识别出四个已知致病性 TMPRSS3 和 GJB2 变异的双重杂合子个体。两个来自不同家庭的个体具有 GJB2 c.35delG 和 TMPRSS3 c.208delC，而另两个来自一个家庭的个体具有 GJB2 c.35delG 以及 TMPRSS3 c.1343T>C 变异。这些个体均未报告过听力问题，其听力状况正常。
我们的数据提供了 TMPRSS3/GJB2 双基因遗传导致 HL 的证据。由于高通量测序越来越多地用于遗传检测，因此应特别谨慎，为患者提供准确的遗传咨询。
