Accurate detection of clinically relevant uniparental disomy from exome sequencing data
Accurate detection of clinically relevant uniparental disomy from exome sequencing data
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DOI：
10.1038/s41436-019-0704-x
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发表时间：
2020-04-01
影响因子：
8.8
通讯作者：
Gilissen, Christian
中科院分区：
文献类型：
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作者：
Yauy, Kevin;de Leeuw, Nicole;Gilissen, Christian
单双亲二染色体（Uniparental disomy， UPD）是一种罕见的来自同一亲本的两条同源染色体，通常通过标记分析或基于单核苷酸多态性（SNP）的微阵列来鉴定。upd可能由于印迹效应、潜在的纯合致病变异或低水平的马赛克非整倍体而导致疾病。在这项研究中，我们在三重奏组和单外显子组测序（ES）数据中检测了临床相关的UPD事件。方法采用基于孟德尔遗传误差的方法对4912个ES三组（所有类型）进行UPD检测，并对29,723个ES单样本（仅等异体）进行纯合性中位数绝对偏差标度区域检测。结果：作为阳性对照，我们准确地鉴定了三个混合UPD，三个异位体，以及两个片段性UPD事件，这些事件之前都是由基于snp的微阵列报道的。此外，我们还发现了3个片段性UPD和11个同染色体事件。这导致了一种基于印记的新诊断，并调整了另一名患者的遗传咨询。结论单ES和三联ES可以很容易地识别UPD，可能与患者有临床相关性。UPD分析应成为临床ES的常规检查，因为它可以提高诊断率并影响遗传咨询。
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.