背景:Array-CGH是全球出生前和出生后发育障碍的第一层遗传测试。不确定显著性的变体(VUS)代表报告的拷贝数变体(CNV)的约10-15%。即使VUS重新分析在实践中变得很常见,没有关于CNV重新解释的长期研究报告.
方法:这项回顾性研究检查了8年(2010-2017年)进行的1641个CGH阵列,以证明定期重新分析不确定意义的CNV的贡献。一方面使用AnnotSV对CNV进行分类,另一方面手动管理。分类基于2020年美国医学遗传学学院(ACMG)标准。
结果:在分析的1641阵列-CGH中,259(15.7%)显示至少一种最初报告的CNV具有不确定的显著性。重新解释后,259例患者中有106例(40.9%)改变了类别,259人中有12人(4.6%)的VUS被重新分类为可能致病或致病.六个是神经发育障碍/自闭症谱系障碍(ASD)的诱发因素。CNV类型(损益)似乎不会影响重分类率,与CNV的长度不同:75%的降级为良性或可能为良性的CNV的大小小于500kb。
结论:这项研究的高重新解释率表明,由于现有数据库的不断丰富,CNV解释自2010年以来迅速发展。重新解释的CNV解释了10例患者的表型,导致最佳遗传咨询。这些发现表明,CNVs应该至少每2年重新解释一次。
Array-CGH is the first-tier genetic test both in pre- and postnatal developmental disorders worldwide. Variants of uncertain significance (VUS) represent around 10~15% of reported copy number variants (CNVs). Even though VUS reanalysis has become usual in practice, no long-term study regarding CNV reinterpretation has been reported.
This retrospective study examined 1641 CGH arrays performed over 8 years (2010-2017) to demonstrate the contribution of periodically re-analyzing CNVs of uncertain significance. CNVs were classified using AnnotSV on the one hand and manually curated on the other hand. The classification was based on the 2020 American College of Medical Genetics (ACMG) criteria.
Of the 1641 array-CGH analyzed, 259 (15.7%) showed at least one CNV initially reported as of uncertain significance. After reinterpretation, 106 of the 259 patients (40.9%) changed categories, and 12 of 259 (4.6%) had a VUS reclassified to likely pathogenic or pathogenic. Six were predisposing factors for neurodevelopmental disorder/autism spectrum disorder (ASD). CNV type (gain or loss) does not seem to impact the reclassification rate, unlike the length of the CNV: 75% of CNVs downgraded to benign or likely benign are less than 500 kb in size.
This study\'s high rate of reinterpretation suggests that CNV interpretation has rapidly evolved since 2010, thanks to the continuous enrichment of available databases. The reinterpreted CNV explained the phenotype for ten patients, leading to optimal genetic counseling. These findings suggest that CNVs should be reinterpreted at least every 2 years.