Genetic etiology analysis of 73 fetuses with ventriculomegaly

Abstract

Objective High-throughput sequencing was performed on 73 fetuses with ventriculomegaly (VM) to analyze the genetic causes, including chromosomal aberrations and genetic variations.Methods The clinical data from fetuses with lateral ventricular width greater than 10 mm in second and third trimester were collected from Shanxi Provincial Children's Hospital between 2020 and 2023. Patient samples included amniotic fluid or miscarriage tissue and were evaluated via copy number variation sequencing (CNV-seq), and those with negative CNV-seq result were further examined using whole exome sequencing (WES), with chromosomal aberrations and genetic variations counted. Statistical analysis was performed using SPSS 26.0, and pregnancy outcomes were followed.Results Of the 73 patients included in the study, 23 (31.5%) cases had chromosomal aberrations with 26 CNV fragments following CNV-seq, including 4 aneuploidies, 12 pathogenic variants, 2 likely pathogenic variants, and 8 variants of unknown significance. The detection rate of chromosomal aberrations was significantly higher in non-isolated VM relative to isolated VM. Negative CNV-seq results (n = 33) were further examined via WES, and a subset (n = 16, 48.48%) contained single-gene defects. These variants included SPATA5, PDHA1, TRIM71, PIK3R2, TUBB, CRB2, PIDD1, RTTN, FGFR3, AIMP1, POGZ, MYH7, CNOT3, MACF1, and PURA, with 9 unreported variant loci also identified.Conclusion VM fetuses have complex developmental outcomes, and thus it is necessary to consider genetic etiology is VM. WES has the potential to provide a genetic diagnosis for VM fetuses without aneuploidy or CNVs, and can thereby increase the fetal VM diagnostic rate.