Detecting novel mutations and combined Klinefelter syndrome in Usher syndrome cases

Abstract

Background: Usher syndrome (USH) is an autosomal recessive disease characterized by hearing loss, vision loss, and occasionally vestibular dysfunction. Klinefelter syndrome (KS) is an X chromosome polyploidy characterized by one or more additional X chromosomes in males. To date, there has been no report of USH combined with KS.

Objectives: This study examined the causative genes in three Chinese probands with congenital hearing loss.

Material and methods: Targeted next-generation sequencing (NGS) was performed to identify mutations in three probands with hearing loss. Low-coverage whole-genome sequencing (WGS) analysis of aneuploidy was used to verify the chromosome aneuploidy.

Results: Four novel MYO7A mutations were identified in two USH1 probands who were initially diagnosed with nonsyndromic hearing loss until the onset of vision loss. Another case was initially diagnosed with nonsyndromic hearing loss and USH2 and KS were discovered incidentally after the genetic analysis.

Conclusions: Our findings expand the mutation spectrum of MYO7A. This is also the first report of concomitant USH and KS. Genetic testing can help with clinical management, particularly if an unrecognized syndromic disorder is identified before the onset of additional symptoms. A clinical genetic evaluation is recommended as part of the diagnostic work-up in congenital hearing loss.

Chinese abstract

背景：Usher综合征（USH）是一种常染色体隐性疾病, 以听力丧失、视力丧失和偶尔前庭功能障碍为特征。Klinefelter综合征（KS）是一种X染色体多倍体疾病, 其特征是男性有一个或多个额外的X染色体。到目前为止, 还没有关于KS和USH并发的报导。

目的：研究中国3例先天性听力损失先证者的致病基因。

材料与方法：采用定向下一代测序技术（NGS）对3例听力丧失先证者进行突变鉴定。采用低覆盖全基因组测序（WGS）方法对染色体非整倍体进行了验证。

结果：在2例USH1先证者中发现4个新的MYO7A突变, 他们最初被诊断为非综合征性听力丧失, 直到视力丧失才改变了诊断。另一个病例最初被诊断为非综合征性听力损失, 经遗传分析偶然发现USH2和KS。

结论：我们的研究结果扩大了MYO7A的突变谱, 这也是USH和KS相随发生的首次报道。基因检测有助于临床治疗, 尤其是在出现其他症状之前发现了一种无法识别的综合征性疾病。临床遗传评估建议成为先天性听力损失诊断工作的一部分。

Keywords:

• Usher syndrome
• USH1
• USH2
• MYO7A
• USH2A
• Klinefelter syndrome

Acknowledgments

We sincerely thank all of the family members for their participation and cooperation in this study.

Disclosure statement

The authors have no financial interests in companies or other entities, and the funders of all grants supporting this article played no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Additional information

Funding

This study was supported by grants from National Key Research and Development Project [2016YFC1000700, 2016YFC1000704] and National Natural Science Foundation of China [81730029] to Pu Dai, National Natural Science Foundation of China [81470683, 81770992] to Weiju Han.