Purpose

Copy-number variants (CNVs) of uncertain clinical significance are routinely reported in a clinical setting only when exceeding predetermined reporting thresholds, typically based on CNV size. Given that very few genes are associated with triplosensitive phenotypes, it is not surprising that many interstitial duplications <1 Mb are found to be inherited and anticipated to be of limited or no clinical significance.

Methods

In an effort to further refine our reporting criteria to maximize diagnostic yield while minimizing the return of uncertain variants, we performed a retrospective analysis of all clinical microarray cases reported in a 10-year window. A total of 1112 reported duplications had parental follow-up, and these were compared by size, RefSeq gene content, and inheritance pattern. De novo origin was used as a rough proxy for pathogenicity.

Results

Approximately 6% of duplications 500 kb–1 Mb were de novo observations, compared with approximately 14% for 1–2 Mb duplications (p = 0.0005). On average, de novo duplications had higher gene counts than inherited duplications.

Conclusion

Our data reveal limited diagnostic utility for duplications of uncertain significance <1 Mb. Considerations for revised reporting criteria are discussed and are applicable to CNVs detected by any genome-wide exploratory methodology, including exome/genome sequencing.

中文翻译：

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<1 Mb 不确定临床意义的重复的有限诊断影响：梅奥诊所报告实践的 10 年回顾性分析。

目的

临床意义不确定的拷贝数变异 (CNV) 只有在超过预先确定的报告阈值（通常基于 CNV 大小）时才会在临床环境中常规报告。鉴于很少有基因与三倍体敏感表型相关，因此发现许多 <1 Mb 的间质重复是遗传的，并且预计其临床意义有限或没有临床意义，这并不奇怪。

方法

为了进一步完善我们的报告标准，以最大限度地提高诊断率，同时最大限度地减少不确定变异的返回，我们对 10 年窗口内报告的所有临床微阵列病例进行了回顾性分析。共有 1112 例报告的重复有父母随访，并通过大小、RefSeq 基因含量和遗传模式进行了比较。从头起源被用作致病性的粗略代表。

结果

大约 6% 的 500 kb-1 Mb 重复是从头观察，而 1-2 Mb 重复大约有 14% ( p  = 0.0005)。平均而言，从头重复的基因计数高于遗传重复。

结论

我们的数据显示，对于意义不确定的重复<1 Mb，诊断效用有限。讨论了修订报告标准的考虑因素，并适用于通过任何全基因组探索方法检测到的 CNV，包括外显子组/基因组测序。