Detection of Clinically Relevant Genetic Variants in Chinese Patients With Nanophthalmos by Trio-Based Whole-Genome Sequencing Study
Detection of Clinically Relevant Genetic Variants in Chinese Patients With Nanophthalmos by Trio-Based Whole-Genome Sequencing Study
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DOI：
10.1167/iovs.18-26275
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发表时间：
2019-07-01
影响因子：
4.4
通讯作者：
Fan, Zhigang
中科院分区：
文献类型：
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作者：
Guo, Congcong;Zhao, Zhenni;Fan, Zhigang
目的.小眼球是一种罕见的遗传性疾病，通常以短眼轴长度（AL）和严重远视为特征。通过孟德尔遗传分析鉴定的突变只能解释一小部分纳米眼病例。我们通过全基因组测序（WGS）研究了小眼球的临床相关遗传变异，包括新生突变（DNMs）和遗传突变。通过WGS分析了来自中国中山眼科中心的11个三人组（11个nanophytic先证者及其未受影响的父母）的临床相关遗传变异。我们进一步筛选了3个三联病例和10个散发病例，以确定MYRF突变。在11个三联体中的两个中，没有证据表明存在有害的遗传常染色体变异，在先证者中鉴定出MYRF的两个DNM（c.789delC，p.S264fs和c.789dupC，p.S264fs）。这些功能丧失的DNM被预测为导致两个先证者中的过早终止密码子和蛋白质结构损伤。此外，在其他9个三人组的8个先证者中发现了PRSS 56和MFRP的有害遗传变异。扩大筛查在一个三人组中发现了额外的MYRF DNM（c.1433G>C，p.R478P），在一个散发病例中发现了停止获得性MYRF突变（c.2956C>T，p.R986X），提示在nanophthalic患者中MYRF突变复发。这是第一个基于trio的nanophthalmos的WGS研究，揭示了DNM在MYRF中的潜在作用以及PRSS 56和MFRP中的罕见遗传变异。MYRF在小眼球发育中的潜在机制需要进一步研究。
PURPOSE. Nanophthalmos is a rare genetic disorder commonly characterized by a short axial length (AL) and severe hyperopia. Mutations that have been identified through Mendelian genetic analysis can only explain a fraction of nanophthalmic cases. We investigate the clinically relevant genetic variants in nanophthalmos by whole-genome sequencing (WGS), including de novo mutations (DNMs) and inherited mutations.METHODS. Clinically relevant genetic variants of 11 trios (11 nanophthalmic probands and their unaffected parents) from the Zhongshan Ophthalmic Center, China, were analyzed by WGS. We further screened three trios and 10 sporadic cases to identify the MYRF mutations.RESULTS. In two of 11 trios, without evidence of the presence of deleterious inherited autosomal variants, two DNMs of MYRF (c.789delC, p.S264fs and c.789dupC, p.S264fs) were identified in the probands. These loss-of-function DNMs were predicted to result in premature stop codons and protein structure damage in both probands. In addition, deleterious inherited genetic variants in PRSS56 and MFRP were found in eight probands of the other nine trios. Expanded screening found an additional MYRF DNM (c.1433G>C, p.R478P) in one trio and a stop-gain MYRF mutation (c.2956C>T, p.R986X) in one sporadic case, suggesting the recurrence of MYRF mutations in nanophthalmic patients.CONCLUSIONS. This is the first trio-based WGS study for nanophthalmos, revealing the potential role of DNMs in MYRF and rare inherited genetic variants in PRSS56 and MFRP. The underlying mechanism of MYRF in the development of nanophthalmos needs to be further investigated.