Purpose

Uniparental disomy (UPD) is the rare occurrence of two homologous chromosomes originating from the same parent and is typically identified by marker analysis or single-nucleotide polymorphism (SNP)-based microarrays. UPDs may lead to disease due to imprinting effects, underlying homozygous pathogenic variants, or low-level mosaic aneuploidies. In this study we detected clinically relevant UPD events in both trio and single exome sequencing (ES) data.

Methods

UPD was detected by applying a method based on Mendelian inheritance errors to a cohort of 4912 ES trios (all UPD types) and by using median absolute deviation–scaled regions of homozygosity to a cohort of 29,723 single ES samples (isodisomy only).

Results

As positive controls, we accurately identified three mixed UPD, three isodisomy, as well as two segmental UPD events that were all previously reported by SNP-based microarrays. In addition, we identified three segmental UPD and 11 isodisomy events. This resulted in a novel diagnosis based on imprinting for one patient, and adjusted genetic counseling for another patient.

Conclusion

UPD can easily be identified using both single and trio ES and may be clinically relevant to patients. UPD analysis should become routine in clinical ES, because it increases the diagnostic yield and could affect genetic counseling.

中文翻译：

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从外显子组测序数据中准确检测临床相关的单亲二体性。

目的

单亲二体 (UPD) 是来自同一亲本的两条同源染色体的罕见情况，通常通过标记分析或基于单核苷酸多态性 (SNP) 的微阵列来识别。由于印记效应、潜在的纯合致病变异或低水平镶嵌非整倍体，UPD 可能导致疾病。在这项研究中，我们在三重和单外显子组测序 (ES) 数据中检测到临床相关的 UPD 事件。

方法

通过将基于孟德尔遗传错误的方法应用于一组 4912 个 ES trios（所有 UPD 类型），并通过对一组 29,723 个单 ES 样本（仅同源性）使用中位绝对偏差缩放纯合区域来​​检测 UPD。

结果

作为阳性对照，我们准确地鉴定了三个混合 UPD、三个同种异构体以及两个节段 UPD 事件，这些事件之前都由基于 SNP 的微阵列报告。此外，我们确定了三个分段 UPD 和 11 个等体事件。这导致了基于对一名患者的印记的新诊断，并为另一名患者调整了遗传咨询。

结论

UPD 可以很容易地使用单个和三个 ES 来识别，并且可能与患者临床相关。UPD 分析应该成为临床 ES 的常规分析，因为它可以提高诊断率并可能影响遗传咨询。