Chenyue Zhao, Huiqin Xue, Jingbo Gao, Min Guo, Hao Yue, Rong Guo, Guizhi Cao, Xiayu Sun, Jianrui Wu
Department of Cytogenetic Laboratory, Children's Hospital of Shanxi, Women Health Center of Shanxi, Taiyuan, China.
School of the Seventh Clinical Medicine, Qingdao Medical College of Qingdao University, Qingdao, China.
Sci Rep. 2025 Jul 2;15(1):23622. doi: 10.1038/s41598-025-06714-2.
To investigate the genetic etiology of ventriculomegaly (VM) in fetuses by analyzing chromosomal aberrations and genetic variations through high-throughput sequencing. Clinical data and samples (amniotic fluid or miscarriage tissue) were collected from fetuses with ventricular width >10 mm, diagnosed at Shanxi Children's Hospital between 2020 and 2023. All samples underwent copy number variation sequencing (CNV-seq), and those with negative CNV-seq result were further analyzed by whole exome sequencing (WES) to identify single-gene variants. Chromosomal abnormalities and monogenic variants were classified according to the American College of Medical Genetics and Genomics guidelines. Statistical analysis was performed using SPSS 26.0, and pregnancy outcomes were tracked. Among 73 VM fetuses, 23 (31.5%) cases exhibited chromosomal aberrations via CNV-seq, including 4 aneuploidies, 12 pathogenic CNVs, 2 likely pathogenic CNVs, and 8 variants of unknown significance. The incidence of chromosomal abnormalities was significantly higher in non-isolated VM fetuses compared to isolated VM (p < 0.05). WES analysis of 33 CNV-negative cases identified single-gene defects in 16 (48.5%) fetuses, including SPATA5, PDHA1, TRIM71, PIK3R2, TUBB, CRB2, PIDD1, RTTN, FGFR3, AIMP1, POGZ, MYH7, CNOT3, MACF1, and PURA gene, with 10 novel variants reported. Fetal VM is associated with heterogeneous neurodevelopmental outcomes, and genetic etiology plays an important role in its pathogenesis. WES enhances the efficiency of diagnosis, particularly for VM fetuses without detectable aneuploidy or CNVs. Identifying the genetic etiology of fetal VM is is crucial for informing birth defect prevention strategies and improving the overall health of the newborn population.
通过高通量测序分析染色体畸变和基因变异，以探究胎儿脑室扩大（VM）的遗传病因。收集了2020年至2023年在山西儿童医院诊断出脑室宽度>10mm的胎儿的临床资料和样本（羊水或流产组织）。所有样本均进行了拷贝数变异测序（CNV-seq），CNV-seq结果为阴性的样本进一步通过全外显子组测序（WES）分析以鉴定单基因变异。根据美国医学遗传学与基因组学学会的指南对染色体异常和单基因变异进行分类。使用SPSS 26.0进行统计分析，并追踪妊娠结局。在73例VM胎儿中，23例（31.5%）通过CNV-seq显示出染色体畸变，包括4例非整倍体、12例致病性CNV、2例可能致病性CNV和8例意义未明的变异。与孤立性VM相比，非孤立性VM胎儿的染色体异常发生率显著更高（p<0.05）。对33例CNV阴性病例的WES分析在16例（48.5%）胎儿中鉴定出单基因缺陷，包括SPATA5、PDHA1、TRIM71、PIK3R2、TUBB、CRB2、PIDD1、RTTN、FGFR3、AIMP1、POGZ、MYH7、CNOT3、MACF1和PURA基因，报告了10个新变异。胎儿VM与异质性神经发育结局相关，遗传病因在其发病机制中起重要作用。WES提高了诊断效率，特别是对于未检测到非整倍体或CNV的VM胎儿。确定胎儿VM的遗传病因对于指导出生缺陷预防策略和改善新生儿总体健康至关重要。
