Abstract：
Objective: To compare the differences between the variation interpretation standards and guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015 (The 2015ACMG/AMP guideline) and the Deafness Specialist Group of the Clinical Genome Resource (ClinGen) in 2018 for hereditary hearing loss (Healing loss, HL) issued the expert specification of the variation interpretation guide (The 2018 HL-EP guideline) in evaluating the pathogenicity of OTOF gene variation in patients with auditory neuropathy. Methods: Thirty-eight auditory neuropathy patients with OTOF gene variant were selected as the study subjects (23 males and 15 females, aged 0.3-25.9 years). Using whole-genome sequencing, whole exome sequencing or target region sequencing (Panel) combined with Sanger sequencing, 38 cases were found to carry more than two OTOF mutation sites. A total of 59 candidate variants were independently interpreted based on the 2015 ACMG/AMP guideline and 2018 HL-EP guideline. Compared with the judgment results in 2015 ACMG/AMP guideline, the variants interpreted as lower pathogenic classifications in the 2018 HL-EP guideline were defined as downgraded variants, and the variants regarded as higher pathogenic classifications were defined as upgraded variants. Statistical analysis was conducted using SPSS 20.0. Results: The concordance rate of variant classification between the guidelines was 72.9%(43/59). The 13.6%(8/59) of variants were upgraded and 13.6% (8/59) of variants downgraded in the classifications of the 2018 HL-EP guideline. A couple of rules saw significant differences between the guidelines (PVS1, PM3, PP2, PP3 and PP5). The distribution of pathogenicity of splicing mutation was statistically different (P=0.013). Conclusions: The 2018 HL-EP guideline is inconsistent with the 2015 ACMG/AMP guideline, when judging the pathogenicity of OTOF gene variants in patients with auditory neuropathy. Through the deletion and refinement of evidence and the breaking of solidification thinking, the 2018 HL-EP guideline makes the pathogenicity grading more traceable and improves the credibility.
目的： 对比2015年美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics，ACMG）和分子病理学会（Association for Molecular Pathology，AMP）发布的变异解读标准与指南（本文中简称2015 ACMG/AMP指南）与2018年临床基因组资源中心（Clinical Genome Resource，ClinGen）耳聋专病小组针对遗传性听力损失（hearing loss，HL）发布的变异解读指南专家规范（本文中简称2018HL专病指南）在评估听神经病患者OTOF基因变异致病性中的异同。 方法： 以38例OTOF基因变异听神经病患者作为研究对象（男23例、女15例，年龄范围0.3~25.9岁），经全基因组重测序、全外显子组测序或目标区域靶向（Panel）测序结合一代Sanger测序验证，38例听神经病患者均检出携带两个以上OTOF变异位点，共计59个候选位点，分别使用2015ACMG/AMP指南以及2018HL专病指南对其致病性进行判断。与2015年指南判断结果相比，2018年指南判断的致病性等级更强定义为升级，更弱定义为降级。采用SPSS 20.0软件进行统计学分析。 结果： 2015 ACMG/AMP指南和2018 HL专病指南的变异分类一致率为72.9%（43/59）。致病性升级变异位点占13.6%（8/59），致病性降级变异位点占13.6%（8/59）。两指南致病性判定不一致主要集中在PVS1、PM3、PP2、PP3以及PP5等级证据的应用上。剪接变异、错义变异、框内插入/缺失以及同义变异致病性分布发生改变，其中剪接变异改变差异具有统计学意义（P=0.013）。 结论： 针对听神经病患者OTOF基因变异进行致病性判断时，2018HL专病指南与2015ACMG/AMP指南存在不一致，2018HL专病指南对证据进行删减及进一步细分，打破常规对于变异类型的固化思维，使得致病性分级更有迹可循，提高可信度。.
目的： 对比2015年美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics，ACMG）和分子病理学会（Association for Molecular Pathology，AMP）发布的变异解读标准与指南（本文中简称2015 ACMG/AMP指南）与2018年临床基因组资源中心（Clinical Genome Resource，ClinGen）耳聋专病小组针对遗传性听力损失（hearing loss，HL）发布的变异解读指南专家规范（本文中简称2018HL专病指南）在评估听神经病患者OTOF基因变异致病性中的异同。 方法： 以38例OTOF基因变异听神经病患者作为研究对象（男23例、女15例，年龄范围0.3~25.9岁），经全基因组重测序、全外显子组测序或目标区域靶向（Panel）测序结合一代Sanger测序验证，38例听神经病患者均检出携带两个以上OTOF变异位点，共计59个候选位点，分别使用2015ACMG/AMP指南以及2018HL专病指南对其致病性进行判断。与2015年指南判断结果相比，2018年指南判断的致病性等级更强定义为升级，更弱定义为降级。采用SPSS 20.0软件进行统计学分析。 结果： 2015 ACMG/AMP指南和2018 HL专病指南的变异分类一致率为72.9%（43/59）。致病性升级变异位点占13.6%（8/59），致病性降级变异位点占13.6%（8/59）。两指南致病性判定不一致主要集中在PVS1、PM3、PP2、PP3以及PP5等级证据的应用上。剪接变异、错义变异、框内插入/缺失以及同义变异致病性分布发生改变，其中剪接变异改变差异具有统计学意义（P=0.013）。 结论： 针对听神经病患者OTOF基因变异进行致病性判断时，2018HL专病指南与2015ACMG/AMP指南存在不一致，2018HL专病指南对证据进行删减及进一步细分，打破常规对于变异类型的固化思维，使得致病性分级更有迹可循，提高可信度。.
摘要：
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