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首页> 外文期刊>Human mutation >Leveraging splice‐affecting variant predictors and a minigene validation system to identify Mendelian disease‐causing variants among exon‐captured variants of uncertain significance
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Leveraging splice‐affecting variant predictors and a minigene validation system to identify Mendelian disease‐causing variants among exon‐captured variants of uncertain significance

机译：利用剪接影响变异预测和微型验证系统，以识别外显子捕获变异的孟德利疾病导致变体的不确定意义的变异

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摘要

Abstract The genetic heterogeneity of Mendelian disorders results in a significant proportion of patients that are unable to be assigned a confident molecular diagnosis after conventional exon sequencing and variant interpretation. Here, we evaluated how many patients with an inherited retinal disease (IRD) have variants of uncertain significance (VUS) that are disrupting splicing in a known IRD gene by means other than affecting the canonical dinucleotide splice site. Three in silico splice‐affecting variant predictors were leveraged to annotate and prioritize variants for splicing functional validation. An in vitro minigene system was used to assay each variant's effect on splicing. Starting with 745 IRD patients lacking a confident molecular diagnosis, we validated 23 VUS as splicing variants that likely explain disease in 26 patients. Using our results, we optimized in silico score cutoffs to guide future variant interpretation. Variants that alter base pairs other than the canonical GT‐AG dinucleotide are often not considered for their potential effect on RNA splicing but in silico tools and a minigene system can be utilized for the prioritization and validation of such splice‐disrupting variants. These variants can be overlooked causes of human disease but can be identified using conventional exon sequencing with proper interpretation guidelines.
机译：摘要孟德尔疾病的遗传异质性导致大部分患者在常规外显子测序和变异解释后无法被分配到自信的分子诊断。在这里，我们评估了遗传性视网膜疾病（IRD）的患者有多少患者具有不确定意义（VUS）的变异，其通过除影响规范二核苷酸接头位点之外，在已知的IRD基因中破坏剪接。利用三个在硅接头变形变体预测器中的三个，以注释和优先考虑用于拼接功能验证的变体。体外微型系统用于测定每个变体对拼接的影响。从745名缺乏自信的分子诊断的IRD患者开始，我们验证了23 VUS作为可能在26名患者中解释病的剪接变体。使用我们的结果，我们优化了Silico评分截止值，以引导未来的变体解释。改变除规范GT-AG二核苷酸之外的基部对的变体通常不考虑它们对RNA剪接的潜在影响，而是在硅工具中，并且在硅基工具中，可以利用微型系统来优先化和验证这种接头破坏变体。这些变体可以被忽视的人类疾病的原因，但可以使用具有适当的解释指南的传统外显子测序来识别。

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  • 来源
    《Human mutation》 |2017年第11期|共13页
  • 作者

    Soens Zachry T.; Branch Justin; Wu Shijing; Yuan Zhisheng; Li Yumei; Li Hui; Wang Keqing; Xu Mingchu; Rajan Lavan; Motta Fabiana L.; Sim?es Renata T.; Lopez‐Solache Irma; Ajlan Radwan; Birch David G.; Zhao Peiquan; Porto Fernanda B.; Sallum Juliana; Koenekoop Robert K.; Sui Ruifang; Chen Rui;

  • 作者单位

    Department of Molecular and Human GeneticsBaylor College of MedicineHouston Texas;

    Department of Molecular and Human GeneticsBaylor College of MedicineHouston Texas;

    Department of OphthalmologyChinese Academy of Medical SciencesBeijing China;

    Department of OphthalmologyChinese Academy of Medical SciencesBeijing China;

    Department of Molecular and Human GeneticsBaylor College of MedicineHouston Texas;

    Department of OphthalmologyChinese Academy of Medical SciencesBeijing China;

    Department of Molecular and Human GeneticsBaylor College of MedicineHouston Texas;

    Department of Molecular and Human GeneticsBaylor College of MedicineHouston Texas;

    Department of Molecular and Human GeneticsBaylor College of MedicineHouston Texas;

    Department of Ophthalmology and Visual SciencesFederal University of S?o PauloS?o Paulo Brazil;

    Department of Retina and VitreousOphthalmologic Center of Minas GeraisBelo Horizonte Minas Gerais;

    McGill Ocular Genetics Laboratory and CentreMcGill University Health CentreMontreal Quebec Canada;

    McGill Ocular Genetics Laboratory and CentreMcGill University Health CentreMontreal Quebec Canada;

    Retina Foundation of the Southwest and Department of OphthalmologyUniversity of Texas Southwestern;

    Department of OphthalmologyXin Hua Hospital affiliated to Shanghai Jiao Tong University School of;

    Department of Retina and VitreousOphthalmologic Center of Minas GeraisBelo Horizonte Minas Gerais;

    Department of Ophthalmology and Visual SciencesFederal University of S?o PauloS?o Paulo Brazil;

    McGill Ocular Genetics Laboratory and CentreMcGill University Health CentreMontreal Quebec Canada;

    Department of OphthalmologyChinese Academy of Medical SciencesBeijing China;

    Department of Molecular and Human GeneticsBaylor College of MedicineHouston Texas;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 医学遗传学;
  • 关键词

    inherited retinal degenerations; minigene; Mendelian disease; molecular diagnosis; noncanonical splicing variants; variants of uncertain significance (VUS);

    机译：遗传性视网膜退化;小烯;孟德梅疾病;分子诊断;非甘露出的拼接变体;意义不确定的变种（VUS）;

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