Abstract：
Clinical exome sequencing (CES) provides a comprehensive and effective analysis of relevant disease-associated genes in a cost-effective manner compared to whole exome sequencing. Although several studies have focused on the diagnostic yield of CES, no study has assessed predictors of CES utility among patients with various Mendelian phenotypes. We assessed the effectiveness of CES as a first-level genetic test for molecular diagnosis in patients with a Mendelian phenotype and explored independent predictors of the clinical utility of CES.
Between January 2016 and December 2019, 603 patients (426 probands and 177 siblings) underwent CES at the Department of Molecular Medicine of the University Hospital of Nancy. The median age of the probands was 34 years (IQR, 12-48), and the proportion of males was 46.9% (200/426). Adults and children represented 64.8% (276/426) and 35.2% (150/426), respectively. The median test-to-report time was 5.6 months (IQR, 4.1-7.2). CES revealed 203 pathogenic or likely pathogenic variants in 160 patients, corresponding to a diagnostic yield of 37.6% (160/426). Independent predictors of CES utility were criteria strongly suggestive of an extreme phenotype, including pediatric presentation and patient phenotypes associated with an increased risk of a priori probability of a monogenic disorder, the inclusion of at least one family member in addition to the proband, and a CES prescription performed by an expert in the field of rare genetic disorders.
Based on a large dataset of consecutive patients with various Mendelian phenotypes referred for CES as a first-tier genetic test, we report a diagnostic yield of ~ 40% and several independent predictors of CES utility that might improve CES diagnostic efficiency.
Between January 2016 and December 2019, 603 patients (426 probands and 177 siblings) underwent CES at the Department of Molecular Medicine of the University Hospital of Nancy. The median age of the probands was 34 years (IQR, 12-48), and the proportion of males was 46.9% (200/426). Adults and children represented 64.8% (276/426) and 35.2% (150/426), respectively. The median test-to-report time was 5.6 months (IQR, 4.1-7.2). CES revealed 203 pathogenic or likely pathogenic variants in 160 patients, corresponding to a diagnostic yield of 37.6% (160/426). Independent predictors of CES utility were criteria strongly suggestive of an extreme phenotype, including pediatric presentation and patient phenotypes associated with an increased risk of a priori probability of a monogenic disorder, the inclusion of at least one family member in addition to the proband, and a CES prescription performed by an expert in the field of rare genetic disorders.
Based on a large dataset of consecutive patients with various Mendelian phenotypes referred for CES as a first-tier genetic test, we report a diagnostic yield of ~ 40% and several independent predictors of CES utility that might improve CES diagnostic efficiency.
摘要：
背景：与全外显子组测序相比，临床外显子组测序（CES）以经济有效的方式提供了对相关疾病相关基因的全面有效的分析。尽管一些研究集中在CES的诊断产量上，尚无研究评估各种孟德尔表型患者CES效用的预测因子.我们评估了CES作为孟德尔表型患者分子诊断的一级遗传测试的有效性，并探索了CES临床应用的独立预测因素。
结果：在2016年1月至2019年12月之间，有603名患者（426名先证者和177名兄弟姐妹）在南希大学医院分子医学系接受了CES。先证者的平均年龄为34岁(IQR，12-48),男性比例为46.9%(200/426)。成人和儿童占64.8%(276/426)和35.2%(150/426)，分别。中位测试报告时间为5.6个月(IQR，4.1-7.2)。CES在160名患者中发现了203种致病性或可能的致病性变异，对应于37.6%(160/426)的诊断率。CES效用的独立预测因子是强烈暗示极端表型的标准，包括儿科表现和患者表型与单基因疾病的先验概率增加的风险相关，除先证外还包括至少一名家庭成员，以及由罕见遗传疾病领域的专家执行的CES处方。
结论：基于大型连续患者的数据集，这些患者具有各种孟德尔表型，被称为CES的第一层遗传测试，我们报告了约40％的诊断率和CES效用的几个独立预测因子，可能会提高CES诊断效率。
结果：在2016年1月至2019年12月之间，有603名患者（426名先证者和177名兄弟姐妹）在南希大学医院分子医学系接受了CES。先证者的平均年龄为34岁(IQR，12-48),男性比例为46.9%(200/426)。成人和儿童占64.8%(276/426)和35.2%(150/426)，分别。中位测试报告时间为5.6个月(IQR，4.1-7.2)。CES在160名患者中发现了203种致病性或可能的致病性变异，对应于37.6%(160/426)的诊断率。CES效用的独立预测因子是强烈暗示极端表型的标准，包括儿科表现和患者表型与单基因疾病的先验概率增加的风险相关，除先证外还包括至少一名家庭成员，以及由罕见遗传疾病领域的专家执行的CES处方。
结论：基于大型连续患者的数据集，这些患者具有各种孟德尔表型，被称为CES的第一层遗传测试，我们报告了约40％的诊断率和CES效用的几个独立预测因子，可能会提高CES诊断效率。
