Institute of Human Genetics, Leipzig University, Leipzig, Germany.
Institute of Human Genetics, Jena University, Jena, Germany.
Hum Genet. 2024 Aug;143(8):955-964. doi: 10.1007/s00439-024-02687-w. Epub 2024 Jul 16.
Uniparental disomy (UPD) is the inheritance of both homologues of a chromosome from only one parent. The detection of UPDs in sequencing data is not well established and a common gap in genetic diagnostics. We applied our in-house UPD detection pipeline to evaluate a cohort of 9212 samples, including multigene panels as well as exome sequencing data in a single, duo or trio constellation. We used the results to inform the design of our publicly available web app altAFplotter. UPDs categorized as heterodisomy, whole chromosome or segmental isodisomy were identified and validated with microsatellites, multiplex ligation-dependent probe amplification as well as Sanger sequencing. We detected 14 previously undiagnosed UPDs including nine isodisomies, four segmental isodisomies as well as one heterodisomy on chromosome 22. We characterized eight findings as potentially causative through homozygous pathogenic variants or imprinting disorders. Overall, our study demonstrates the utility of our UPD detection pipeline with our web app, altAFplotter, to reliably identify UPDs. This not only increases the diagnostic yield of cases with growth and metabolic disturbances, as well as developmental delay, but also enhances the understanding of UPDs that may be relevant for recurrence risks and genetic counseling.
单亲二体 (UPD) 是指从一个亲本中遗传两条同源染色体。测序数据中 UPD 的检测尚未得到很好的建立，这是遗传诊断中的一个常见空白。我们应用内部的 UPD 检测管道来评估了 9212 个样本的队列，包括多基因面板以及在单个、双亲和三亲的组合中的外显子测序数据。我们使用这些结果来为我们的公共可用的网络应用 altAFplotter 提供设计信息。我们使用微卫星、多重连接依赖性探针扩增以及 Sanger 测序来鉴定和验证归类为异源二体、整条染色体或片段同二体的 UPD。我们检测到了 14 个先前未诊断的 UPD，包括 9 个同二体、4 个片段同二体和 1 个 22 号染色体的异源二体。我们通过纯合致病性变异或印迹障碍特征化了 8 个发现为潜在的致病原因。总体而言，我们的研究展示了我们的 UPD 检测管道和我们的网络应用 altAFplotter 的实用性，可可靠地识别 UPD。这不仅增加了具有生长和代谢紊乱以及发育迟缓的病例的诊断产量，还增强了对可能与复发风险和遗传咨询相关的 UPD 的理解。
