We present a comprehensive clinically oriented workflow for large-insert genome sequencing (liGS)-based nucleotide level resolution and interpretation of de novo (dn) apparently balanced chromosomal abnormalities (BCA) in prenatal diagnosis (PND). Retrospective or concomitant with conventional PND and liGS, molecular and newly developed clinically inspired bioinformatic tools (TAD-GConTool and CNV-ConTool) are applied to analyze and assess the functional and phenotypic outcome of dn structural variants (dnSVs). Retrospective analysis of four phenotype-associated dnSVs identified during conventional PND precisely reveal the genomic elements disrupted by the translocation breakpoints. Identification of autosomal dominant disease due to the disruption of ANKS1B and WDR26 by t(12;17)(q23.1;q21.33)dn and t(1;3)(q24.11;p25.3)dn breakpoints, respectively, substantiated the proposed workflow. We then applied this workflow to two ongoing prenatal cases with apparently balanced dnBCAs: 46,XX,t(16;17)(q24;q21.3)dn referred for increased risk on combined first trimester screening and 46,XY,t(2;19)(p13;q13.1)dn referred due to a previous trisomy 21 pregnancy. Translocation breakpoints in the t(16;17) involve ANKRD11 and WNT3 and disruption of ANKRD11 resulted in KBG syndrome confirmed in postnatal follow-up. Breakpoints in the t(2;19) are within ATP6V1B1 and the 3' UTR of CEP89, and are not interpreted to cause disease. Genotype-phenotype correlation confirms the causative role of WDR26 in the Skraban-Deardorff and 1q41q42 microdeletion phenocopy syndromes, and that disruption of ANKS1B causes ANKS1B haploinsufficiency syndrome. In sum, we show that an liGS-based approach can be realized in PND care providing additional information concerning clinical outcomes of dnBCAs in patients with such rearrangements.

中文翻译：

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全面的临床导向工作流程，用于在基因组景观中从头明显平衡的染色体易位的产前诊断中进行核苷酸水平分辨率和解释。

我们提出了一个全面的临床导向工作流程，用于产前诊断 (PND) 中基于大插入基因组测序 (liGS) 的核苷酸水平分辨率和从头 (dn) 明显平衡染色体异常 (BCA) 的解释。回顾性或与传统 PND 和 liGS 相结合，分子和新开发的临床启发生物信息学工具（TAD-GConTool 和 CNV-ConTool）用于分析和评估 dn 结构变异（dnSV）的功能和表型结果。对传统 PND 期间鉴定的四种表型相关 dnSV 的回顾性分析精确揭示了易位断点破坏的基因组元件。分别通过 t(12;17)(q23.1;q21.33)dn 和 t(1;3)(q24.11;p25.3)dn 断点破坏 ANKS1B 和 WDR26 来鉴定常染色体显性遗传病，证实了建议的工作流程。然后，我们将此工作流程应用于两个正在进行的产前病例，其 dnBCA 明显平衡：46,XX,t(16;17)(q24;q21.3)dn 指联合妊娠早期筛查的风险增加，46,XY,t(2 ;19)(p13;q13.1)dn 因之前 21 三体妊娠而转介。t(16;17) 中的易位断点涉及 ANKRD11 和 WNT3，ANKRD11 的破坏导致产后随访中证实的 KBG 综合征。t(2;19) 中的断点位于 ATP6V1B1 和 CEP89 的 3' UTR 内，并且不会解释为导致疾病。基因型-表型相关性证实了 WDR26 在 Skraban-Deardorff 和 1q41q42 微缺失表型综合征中的致病作用，并且 ANKS1B 的破坏导致 ANKS1B 单倍体不足综合征。总之，我们表明基于 liGS 的方法可以在 PND 护理中实现，提供有关此类重排患者 dnBCA 临床结果的更多信息。