Federico Ferraro, Nikolas Kühn, Dmitrijs Rots, Herma C van der Linde, Banin Mohseni, Leontine van Unen, Mark Drost, Mark Nellist, Marieke Koekkoek, Rachel Schot, Henriette W de Gier, Mieke Pleumeekers, Tahsin Stefan Barakat, Tjitske Kleefstra, Marjolein Weerts, Marieke F van Dooren, Tjakko J van Ham
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引用次数: 0
摘要
Treacher Collins综合征（TCS）是一种颅面遗传疾病，由TCOF1、POLR1B、POLR1C或POLR1D的功能变异丧失引起。在这里，我们描述了两个以前未确诊的父亲同父异母兄弟姐妹感染临床TCS，和他们的父亲显然未受影响。诊断性短读rna测序（srRNA-Seq）鉴定了TCOF1的异常表达，光学基因组定位检测到其中有一个大的基因组插入。长读基因组测序（lrGS）在TCOF1的17号内含子中发现了一个深3.5 kb的sin - vntr - alu （SVA）反转录转座子插入。长读RNA-seq （lrRNA-Seq）显示，插入部分外显子化，诱导了短的非规范TCOF1异构体c的转换。sva插入在两个同父异母兄弟姐妹中都得到了证实，我们在父亲身上检测到了镶嵌现象。这项工作证明了lrRNA-Seq和lrGS在鉴定不明原因遗传疾病的致病变异方面的潜力。
Long-read DNA and RNA sequencing reveal an intronic retrotransposon insertion in TCOF1 causing Treacher Collins syndrome.
Treacher Collins syndrome (TCS) is a craniofacial genetic disorder caused by loss of function variants in TCOF1, POLR1B, POLR1C or POLR1D. Here we describe two previously undiagnosed paternal half-siblings affected with clinical TCS, and their apparently unaffected father. Diagnostic short-read RNA-sequencing (srRNA-Seq) identified aberrant expression of TCOF1 and optical genome mapping detected a large genomic insertion therein. Long-read genome sequencing (lrGS) resolved a deep intronic 3.5 kb SINE-VNTR-Alu (SVA) retrotransposon insertion in intron 17 of TCOF1. Long-read RNA-seq (lrRNA-Seq) demonstrated that the insertion was partially exonized inducing isoform switch to the shorter non-canonical TCOF1 isoform c. SVA-insertion was confirmed in both half-siblings, and we detected mosaicism in the father. This work demonstrates the potential of lrRNA-Seq and lrGS, to identify pathogenic variants in unexplained genetic disorders.
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