Austin-Tse Christina A, Mandelker Diana L, Oza Andrea M, Mason-Suares Heather, Rehm Heidi L, Amr Sami S
Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MA 02129, USA; Harvard Medical School Genetics Training Program, Boston, MA 02115, USA.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Eur J Med Genet. 2018 Oct;61(10):621-626. doi: 10.1016/j.ejmg.2018.04.006. Epub 2018 Apr 12.
Given that all forms of Usher syndrome (USH) present with hearing loss in advance of retinal disease, the syndromic nature of the disorder is rarely appreciated when critical management decisions are being made. As a result, molecular diagnostics are crucial in guiding the management of USH patients. While 11 genes have been associated with USH, the USH2A gene is one of the largest contributors. Approximately 20% of suspected USH probands that undergo USH2A sequencing at our laboratory receive an inconclusive result due to the identification of a monoallelic disease-causing variant in USH2A. Many studies suggest that intragenic deletions and duplications represent an important USH2A variant type that can be missed by sequencing assays if supplemental algorithms or testing methods are not applied. To gain a comprehensive view of the contribution of USH2A CNVs to USH, we conducted prospective and retrospective screening in 700 hearing loss probands. Fourteen individuals with 11 unique USH2A CNVs are reported, including one pathogenic multi-exon duplication. Additionally, we mapped deletion breakpoints and performed a meta-analysis of USH2A CNVs to evaluate recurrence and underlying mechanisms. This analysis revealed breakpoint grouping within three introns, raising the possibility of CNV-susceptible regions within the gene. Overall, our data highlight the diversity of pathogenic CNVs in this gene, demonstrating that the comprehensive, high-resolution USH2A CNV analysis methods employed here are essential components of clinical genetic testing for USH.
鉴于所有类型的Usher综合征（USH）在视网膜疾病出现之前就已出现听力损失，在做出关键管理决策时，这种疾病的综合征性质很少得到重视。因此，分子诊断对于指导USH患者的管理至关重要。虽然已有11个基因与USH相关，但USH2A基因是最大的致病因素之一。在我们实验室对疑似USH先证者进行USH2A测序时，约20%的患者由于在USH2A中鉴定出单等位基因致病变异而得到不确定的结果。许多研究表明，基因内缺失和重复是一种重要的USH2A变异类型，如果不应用补充算法或检测方法，测序分析可能会遗漏这种变异。为了全面了解USH2A拷贝数变异（CNV）对USH的影响，我们对700名听力损失先证者进行了前瞻性和回顾性筛查。报告了14名携带11种独特USH2A CNV的个体，包括1例致病性多外显子重复。此外，我们绘制了缺失断点，并对USH2A CNV进行了荟萃分析，以评估复发情况和潜在机制。该分析揭示了三个内含子内的断点分组，提示该基因内存在CNV易感区域。总体而言，我们的数据突出了该基因致病CNV的多样性，表明这里采用的全面、高分辨率USH2A CNV分析方法是USH临床基因检测的重要组成部分。
