Abstract：
The advent of next-generation sequencing (NGS) has enhanced the diagnostic efficacy for monogenic diseases, while presenting challenges in achieving consistent diagnoses.
We retrospectively analyzed the concordance rate and reasons for the inconsistency between the original diagnostic result from the genetic testing laboratory and the variant validation result from the prenatal diagnostic center. The validation procedure comprised three stages: validation of variant detection, reevaluation of variant classification, and assessment of recurrence risk, which involved verifying the mode of inheritance and parental carriage.
In total, 17 (6%) of the 286 families affected by rare monogenic diseases showed different results during the variant validation procedure. These cases comprised four (23.5%) with variant detection errors, 12 (70.5%) with inconsistent interpretation, and one (6%) with non-Mendelian inheritance patterns. False-positive NGS results confirmed by Sanger sequencing were related to pseudogenes and GC-rich regions. The classification of the 17 variants was altered in the 12 cases owing to various factors. The case with an atypical inheritance pattern was originally considered autosomal recessive inheritance, but was diagnosed as maternal uniparental disomy after additional genetic analysis.
We underscored the significance of variant validation by prenatal diagnostic centers. Families affected by monogenic diseases with reproductive plans should be referred to prenatal genetic centers as early as possible to avoid different results that may postpone subsequent prenatal diagnosis.
We retrospectively analyzed the concordance rate and reasons for the inconsistency between the original diagnostic result from the genetic testing laboratory and the variant validation result from the prenatal diagnostic center. The validation procedure comprised three stages: validation of variant detection, reevaluation of variant classification, and assessment of recurrence risk, which involved verifying the mode of inheritance and parental carriage.
In total, 17 (6%) of the 286 families affected by rare monogenic diseases showed different results during the variant validation procedure. These cases comprised four (23.5%) with variant detection errors, 12 (70.5%) with inconsistent interpretation, and one (6%) with non-Mendelian inheritance patterns. False-positive NGS results confirmed by Sanger sequencing were related to pseudogenes and GC-rich regions. The classification of the 17 variants was altered in the 12 cases owing to various factors. The case with an atypical inheritance pattern was originally considered autosomal recessive inheritance, but was diagnosed as maternal uniparental disomy after additional genetic analysis.
We underscored the significance of variant validation by prenatal diagnostic centers. Families affected by monogenic diseases with reproductive plans should be referred to prenatal genetic centers as early as possible to avoid different results that may postpone subsequent prenatal diagnosis.
摘要：
背景：下一代测序（NGS）的出现增强了对单基因疾病的诊断效能，在实现一致诊断方面面临挑战。
方法：我们回顾性分析了基因检测实验室的原始诊断结果与产前诊断中心的变异验证结果之间的一致率和不一致的原因。验证程序包括三个阶段：变体检测的验证，变体分类的重新评估，和复发风险评估，其中涉及验证继承和父母运输的方式。
结果：总计，在变异验证程序中，受罕见单基因疾病影响的286个家庭中有17个（6％）显示出不同的结果。这些病例包括4例(23.5%)变异体检测错误，12（70.5%），解释不一致，和一个(6%)具有非孟德尔遗传模式。通过Sanger测序证实的假阳性NGS结果与假基因和富含GC的区域有关。由于各种因素，12例病例中17种变体的分类发生了改变。非典型遗传模式的病例最初被认为是常染色体隐性遗传，但在额外的遗传分析后被诊断为母亲单亲二体。
结论：我们强调了产前诊断中心变异验证的重要性。受具有生殖计划的单基因疾病影响的家庭应尽早转介到产前遗传中心，以避免可能推迟后续产前诊断的不同结果。
方法：我们回顾性分析了基因检测实验室的原始诊断结果与产前诊断中心的变异验证结果之间的一致率和不一致的原因。验证程序包括三个阶段：变体检测的验证，变体分类的重新评估，和复发风险评估，其中涉及验证继承和父母运输的方式。
结果：总计，在变异验证程序中，受罕见单基因疾病影响的286个家庭中有17个（6％）显示出不同的结果。这些病例包括4例(23.5%)变异体检测错误，12（70.5%），解释不一致，和一个(6%)具有非孟德尔遗传模式。通过Sanger测序证实的假阳性NGS结果与假基因和富含GC的区域有关。由于各种因素，12例病例中17种变体的分类发生了改变。非典型遗传模式的病例最初被认为是常染色体隐性遗传，但在额外的遗传分析后被诊断为母亲单亲二体。
结论：我们强调了产前诊断中心变异验证的重要性。受具有生殖计划的单基因疾病影响的家庭应尽早转介到产前遗传中心，以避免可能推迟后续产前诊断的不同结果。
