Purpose

Existing research suggests that while some laboratories report variants of uncertain significance, unsolicited findings (UF), and/or secondary findings (SF) when performing exome sequencing, others do not.

Methods

To investigate reporting differences, we created virtual patient–parent trio data by merging variants from patients into “normal” exomes. We invited laboratories worldwide to analyze the data along with patient phenotype information (developmental delay, dysmorphic features, and cardiac hypertrophy). Laboratories issued a diagnostic exome report and completed questionnaires to explain their rationale for reporting (or not reporting) each of the eight variants integrated.

Results

Of the 39 laboratories that completed the questionnaire, 30 reported the HDAC8 variant, which was a partial cause of the patient’s primary phenotype, and 26 reported the BICD2 variant, which explained another phenotypic component. Lack of reporting was often due to using a filter or a targeted gene panel that excluded the variant, or because they did not consider the variant to be responsible for the phenotype. There was considerable variation in reporting variants associated with the cardiac phenotype (MYBPC3 and PLN) and reporting UF/SF also varied widely.

Conclusion

This high degree of variability has significant impact on whether causative variants are identified, with important implications for patient care.

中文翻译：

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使用虚拟患者的质量评估分析实验室报告实践

目的

现有研究表明，虽然一些实验室在进行外显子组测序时报告了意义不确定的变异、未经请求的发现 (UF) 和/或二次发现 (SF)，但其他实验室却没有。

方法

为了调查报告差异，我们通过将来自患者的变异合并到“正常”外显子组中来创建虚拟的患者-父母三人组数据。我们邀请世界各地的实验室分析数据以及患者表型信息（发育迟缓、畸形特征和心脏肥大）。实验室发布了一份诊断外显子组报告并完成了调查问卷，以解释他们报告（或不报告）整合的八种变体中的每一种的理由。

结果

在完成问卷的 39 个实验室中，30 个报告了HDAC8变异，这是患者主要表型的部分原因，26 个报告了BICD2变异，这解释了另一个表型成分。缺乏报告通常是由于使用了排除变异的过滤器或靶向基因组，或者因为他们不认为变异是造成表型的原因。报告的与心脏表型（ MYBPC3和PLN ）相关的变异有很大差异，报告的 UF/SF 也有很大差异。

结论

这种高度的变异性对是否确定致病变异具有重大影响，对患者护理具有重要意义。