Yue Fagui, Yang Xiao, Liu Ning, Liu Ruizhi, Zhang Hongguo
Center for Reproductive Medicine and Center for Prenatal Diagnosis, First Hospital, Jilin University, Changchun, China.
Jilin Engineering Research Center for Reproductive Medicine and Genetics, Jilin University, Changchun, China.
Front Med (Lausanne). 2024 May 9;11:1349171. doi: 10.3389/fmed.2024.1349171. eCollection 2024.
Genetic etiology plays a critical role in fetal ventriculomegaly (VM). However, the studies on chromosomal copy number variants (CNVs) in fetal VM are limited. This study aimed to investigate the chromosomal CNVs in fetuses with mild to moderate VM, and explore its genotype-phenotype correlation.
A total of 242 fetuses with mild to moderate VM detected by prenatal ultrasound were enrolled in our study from October 2018 to October 2022. All cases underwent chromosomal microarray analysis (CMA) and G-banding simultaneously. All VM cases were classified different subgroups according to the maternal age, severity, VM distribution and presence/absence of other ultrasound abnormalities. The pregnancy outcomes and health conditions after birth were followed up. We also performed a pooled analysis regarding likely pathogenic and pathogenic CNVs (LP/P CNVs) for VM.
The detection rate of chromosomal abnormalities by karyotyping was 9.1% (22/242), whereas it was 16.5% (40/242) when CMA was conducted ( < 0.05). The total detection rate of chromosomal abnormalities by karyotyping and CMA was 21.1% (51/242). A 12.0% incremental yield of CMA over karyotyping was observed. The detection rate of total genetic variants in fetuses with bilateral VM was significantly higher than in fetuses with unilateral VM (30.0% vs. 16.7%, = 0.017). No significant differences were discovered between isolated VM and non-isolated VM, or between mild and moderate VM, or between advanced maternal age (AMA) and non-AMA (all > 0.05). 28 fetuses with VM were terminated and 214 fetuses were delivered: one presented developmental delay and one presented congenital heart disease. The VM cases with both positive CMA and karyotypic results had a higher rate of termination of pregnancy than those with either a positive CMA or karyotypic result, or both negative testing results ( < 0.001).
The combination of CMA and karyotyping should be adopted to improve the positive detection rate of chromosomal abnormalities for VM. The total genetic abnormalities detected using both techniques would affect the final pregnancy outcomes. LP/P CNVs at 16p11.2, 17p13, and 22q11.21 were identified as the top three chromosomal hotspots associated with VM, which would enable genetic counselors to provide more precise genetic counseling for VM pregnancies.
遗传病因在胎儿脑室扩大（VM）中起关键作用。然而，关于胎儿VM中染色体拷贝数变异（CNV）的研究有限。本研究旨在调查轻度至中度VM胎儿的染色体CNV，并探讨其基因型与表型的相关性。
2018年10月至2022年10月，共有242例经产前超声检测为轻度至中度VM的胎儿纳入本研究。所有病例同时进行染色体微阵列分析（CMA）和G显带分析。所有VM病例根据母亲年龄、严重程度、VM分布以及是否存在其他超声异常分为不同亚组。对妊娠结局和出生后的健康状况进行随访。我们还对VM的可能致病和致病CNV（LP/P CNV）进行了汇总分析。
核型分析检测染色体异常的检出率为9.1%（22/242），而进行CMA时为16.5%（40/242）（P<0.05）。核型分析和CMA检测染色体异常的总检出率为21.1%（51/242）。观察到CMA比核型分析的检出率提高了12.0%。双侧VM胎儿的总基因变异检出率显著高于单侧VM胎儿（30.0%对16.7%，P=0.017）。孤立性VM与非孤立性VM之间、轻度与中度VM之间、高龄产妇（AMA）与非AMA之间均未发现显著差异（均P>0.05）。28例VM胎儿终止妊娠，214例胎儿分娩：1例出现发育迟缓，1例出现先天性心脏病。CMA和核型结果均为阳性的VM病例终止妊娠的比率高于CMA或核型结果为阳性之一或两者检测结果均为阴性的病例（P<0.001）。
应采用CMA和核型分析相结合的方法提高VM染色体异常的阳性检出率。两种技术检测到的总基因异常会影响最终的妊娠结局。16p11.2、17p13和22q11.21处的LP/P CNV被确定为与VM相关的前三大染色体热点，这将使遗传咨询师能够为VM妊娠提供更精确的遗传咨询。
