Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China.
Department of Ophthalmology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
J Cell Mol Med. 2020 Jul;24(14):7743-7750. doi: 10.1111/jcmm.15405. Epub 2020 May 25.
Usher syndrome encompasses a group of genetically and clinically heterogeneous autosomal recessive disorders with hearing deficiencies and retinitis pigmentosa. The mechanisms underlying the Usher syndrome are highly variable. In the present study, a Chinese family with Usher syndrome was recruited. Whole exome sequencing (WES), Sanger sequencing, homozygosity mapping, short tandem repeat (STR) analysis and segregation analysis were performed. Functional domains of the pathogenic variant for USH2A were analysed. We identified a homozygous frameshift variant c.99_100insT (p.Arg34Serfs41) in the USH2A gene in the proband that showed discordant segregation in the father. Further homozygosity mapping and STR analysis identified an unusual homozygous variant of proband that originated from maternal uniparental disomy (UPD). The p.Arg34Serfs41 variant produced a predicted truncated protein that removes all functional domains of USH2A. The variant was not included in the 1000 Human Genomes Project database, ExAC database, HGMD or gnomAD database, but was included in the ClinVar databases as pathogenic. Although USH2A is an autosomal recessive disease, the effects of UPD should be informed in genetic counselling since the recurrence risk of an affected child is greatly reduced when the disease is due to the UPD mechanism. To test potential patients, WES, combined with STR analysis and homozygosity mapping, provides an accurate and useful strategy for genetic diagnosis. In summary, our discoveries can help further the understanding of the molecular pathogenesis of Usher syndrome type IIA to advance the prevention, diagnosis and therapy for this disorder.
Usher 综合征包括一组具有遗传和临床异质性的常染色体隐性遗传病，具有听力缺陷和视网膜色素变性。Usher 综合征的发病机制高度可变。本研究招募了一个有 Usher 综合征的中国家庭。进行了全外显子组测序（WES）、Sanger 测序、纯合子作图、短串联重复（STR）分析和分离分析。对致病性 USH2A 变异体的功能域进行了分析。我们在先证者中发现了 USH2A 基因中的纯合移码变异 c.99_100insT（p.Arg34Serfs41），该变异在父亲中表现出不一致的分离。进一步的纯合子作图和 STR 分析确定了先证者的一个异常纯合变异，该变异来源于母源性单亲二体（UPD）。p.Arg34Serfs41 变异产生了一种预测的截断蛋白，该蛋白去除了 USH2A 的所有功能域。该变异未包含在 1000 个人类基因组计划数据库、ExAC 数据库、HGMD 或 gnomAD 数据库中，但包含在 ClinVar 数据库中，被认为是致病性的。尽管 USH2A 是一种常染色体隐性疾病，但 UPD 的影响应在遗传咨询中告知，因为当疾病是由于 UPD 机制引起时，受影响孩子的复发风险大大降低。为了测试潜在的患者，WES 结合 STR 分析和纯合子作图，为遗传诊断提供了一种准确和有用的策略。总之，我们的发现有助于进一步了解 IIA 型 Usher 综合征的分子发病机制，为该疾病的预防、诊断和治疗提供帮助。
