Purpose

Automated variant filtering is an essential part of diagnostic genome-wide sequencing but may generate false negative results. We sought to investigate whether some previously identified pathogenic variants may be being routinely excluded by standard variant filtering pipelines.

Methods

We evaluated variants that were previously classified as pathogenic or likely pathogenic in ClinVar in known developmental disorder genes using exome sequence data from the Deciphering Developmental Disorders (DDD) study.

Results

Of these ClinVar pathogenic variants, 3.6% were identified among 13,462 DDD probands, and 1134/1352 (83.9%) had already been independently communicated to clinicians using DDD variant filtering pipelines as plausibly pathogenic. The remaining 218 variants failed consequence, inheritance, or other automated variant filters. Following clinical review of these additional variants, we were able to identify 112 variants in 107 (0.8%) DDD probands as potential diagnoses.

Conclusion

Lower minor allele frequency (<0.0005%) and higher gold star review status in ClinVar (>1 star) are good predictors of a previously identified variant being plausibly diagnostic for developmental disorders. However, around half of previously identified pathogenic variants excluded by automated variant filtering did not appear to be disease-causing, underlining the continued need for clinical evaluation of candidate variants as part of the diagnostic process.

中文翻译：

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评估 DDD 研究中 ClinVar 中归类为致病性的变异

目的

自动变异过滤是诊断全基因组测序的重要组成部分，但可能会产生假阴性结果。我们试图调查一些先前发现的致病变异是否可能被标准变异过滤管道常规排除。

方法

我们使用破译发育障碍 (DDD) 研究的外显子组序列数据，评估了已知发育障碍基因中先前在 ClinVar 中被分类为致病性或可能致病性的变异。

结果

在这些 ClinVar 致病变异中，有 3.6% 在 13,462 名 DDD 先证者中被鉴定出来，并且 1134/1352 (83.9%) 已经使用 DDD 变异过滤管道独立地传达给临床医生，认为其可能致病。其余 218 个变体未能通过后果、继承或其他自动变体过滤器。对这些额外变异进行临床审查后，我们能够在 107 名 (0.8%) DDD 先证者中识别出 112 种变异作为潜在的诊断。

结论

ClinVar 中较低的次要等位基因频率 (<0.0005%) 和较高的金星评审状态 (>1 星) 是先前识别的变异的良好预测因子，该变异可能诊断发育障碍。然而，之前通过自动变异过滤排除的约一半的致病变异似乎并不致病，这强调了作为诊断过程的一部分，仍然需要对候选变异进行临床评估。