Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
Department of Pediatrics, Juntendo University Urayasu Hospital, Chiba, Japan.
Congenit Anom (Kyoto). 2021 May;61(3):76-81. doi: 10.1111/cga.12400. Epub 2020 Nov 24.
Chimeric transcripts are formed by chromosomal aberrations. Little is known about the role of chimeric transcripts in the pathogenesis of birth defects. We reanalyzed RNA-seq data in alignment map files from the peripheral blood of 56 patients in whom the diagnoses could not be confirmed by standard exome analysis and transcriptome analysis to screen for chimeric transcripts using a dedicated software, ChimPipe. Chimeric analysis led to a diagnosis in two of the 56 patients: (a) the first patient had a chimeric transcript spanning the causative gene ZEB2 and the GTDC1 gene in its neighboring locus. RNA-seq revealed reads spanning exon 5 of ZEB2 and exon 7 of GTDC1. Whole genome sequencing revealed a 436-kb deletion spanning intron 4 of ZEB2 and intron 7 of GTDC1 and the diagnosis of Mowat-Wilson syndrome was made. (b) The second patient had a chimeric transcript spanning the causative gene KCNK9 and the TRAPPC9 gene in its neighboring locus. RNA-seq revealed reads spanning exon 21 of TRAPPC9 and exon 1 of KCNK9. Whole genome sequencing revealed a 186-kb deletion spanning intron 20 of TRAPPC9 and intron 1 of KCNK9 in this patient. KCNK9 gene is a maternally expressed imprinted gene. The diagnosis of Birk-Barel syndrome was made. Thus, both patients had chimeric transcripts that were directly involved in the pathogenesis of the birth defects. The approach reported herein, of detecting chimeric transcripts from RNA-seq data, is unique in that the approach does not rely on any prior information on the presence of genomic deletion.
嵌合转录本是由染色体畸变形成的。关于嵌合转录本在出生缺陷发病机制中的作用知之甚少。我们重新分析了 56 名患者外周血的 RNA-seq 数据，这些患者的诊断无法通过标准外显子组分析和转录组分析确认，使用专用软件 ChimPipe 在对齐图文件中筛选嵌合转录本。嵌合分析导致 56 名患者中的 2 名患者得到诊断：（a）第 1 名患者存在跨越致病基因 ZEB2 和其邻近基因 GTDC1 的嵌合转录本。RNA-seq 显示跨越 ZEB2 外显子 5 和 GTDC1 外显子 7 的读段。全基因组测序显示跨越 ZEB2 内含子 4 和 GTDC1 内含子 7 的 436-kb 缺失，诊断为 Mowat-Wilson 综合征。（b）第 2 名患者存在跨越致病基因 KCNK9 和其邻近基因 TRAPPC9 的嵌合转录本。RNA-seq 显示跨越 TRAPPC9 外显子 21 和 KCNK9 外显子 1 的读段。全基因组测序显示该患者跨越 TRAPPC9 内含子 20 和 KCNK9 内含子 1 的 186-kb 缺失。KCNK9 基因是一个母系表达的印记基因。诊断为 Birk-Barel 综合征。因此，这两名患者都有直接参与出生缺陷发病机制的嵌合转录本。本文报道的从 RNA-seq 数据中检测嵌合转录本的方法是独特的，因为该方法不依赖于任何关于基因组缺失存在的先验信息。
