Abstract：
Zic family member 1 (ZIC1), a gene located on chromosome 3q24, encodes a transcription factor with zinc finger domains that is essential for the normal development of the cerebellum. Heterozygous loss-of-function of ZIC1 causes Dandy-Walker malformation, while heterozygous gain-of-function leads to a multiple congenital anomaly syndrome characterized by craniosynostosis, brain abnormalities, facial features, and learning disability. In this study, we present the results of genetic analysis of a male patient with clinically suspected Gomez-Lopez-Hernandez syndrome. The patient displayed multiple congenital abnormalities, including bicoronal craniosynostosis, characteristic facial features, cerebellar malformation with rhombencephalosynapsis, and temporal alopecia, and a de novo inversion of chromosome 3q. Breakpoint analysis using a Nanopore long-read sequencer revealed a breakpoint in the distal centromere of 3q24 located 7 kb downstream of the 3\' untranslated region of ZIC1. On the basis of the clinical similarities, we concluded that the abnormalities in this patient were caused by the transcriptional dysregulation of ZIC1. We hypothesize the underlying molecular mechanisms of transcriptional dysregulation of ZIC1 such as the abnormalities in topologically associated domains encompassing ZIC1. This study highlights the usefulness of long-read sequencing in the analysis of de novo balanced chromosomal abnormalities.
摘要：
Zic家族成员1（ZIC1），位于染色体3q24上的一个基因，编码一个具有锌指结构域的转录因子，这是小脑正常发育所必需的。ZIC1的杂合功能丧失导致Dandy-Walker畸形，而杂合功能获得导致以颅骨融合为特征的多发性先天性异常综合征，大脑异常,面部特征,学习障碍。在这项研究中,我们对1例临床怀疑为Gomez-Lopez-Hernandez综合征的男性患者进行基因分析.患者表现出多种先天性异常，包括双冠状颅骨融合,特征性的面部特征，小脑畸形伴菱形脑突触，和颞性脱发，和3q染色体的从头倒位。使用Nanopore长读数测序仪的断点分析显示，位于ZIC13'非翻译区下游7kb的3q24远端着丝粒中的断点。根据临床相似性，我们得出结论,该患者的异常是由ZIC1的转录失调引起的.我们假设ZIC1转录失调的潜在分子机制，例如包含ZIC1的拓扑相关结构域的异常。这项研究强调了长读数测序在从头平衡染色体异常分析中的有用性。
