Genetic etiology analysis of 244 fetal ventricular septal defect in the prenatal setting

Abstract

Objective This study evaluated the application of karyotyping combined with single-nucleotide polymorphism (SNP) array and whole-exome sequencing (WES) of prenatal diagnosis of ventricular septal defect (VSD), and explored the genetic etiology of VSD. Methods 244 fetuses with VSD diagnosed by prenatal echocardiography were selected, including 59 cases isolated VSD and 185 cases non-isolated VSD, and used for conventional karyotyping and SNP analysis at the same time. Among them, 19 fetuses were used for further Trio-WES detection. Results 20 chromosomal abnormality were identified by karyotyping/SNP array. Another 21 cases of abnormal copy number variations (CNVs) were identified by SNP array, including 10 cases of pathogenic CNVs and 11 cases of variations of uncertain significance (VUS). 5 cases with (likely) pathogenic genetic variants were identified by Trio-WES. The detection rate of pathogenic chromosomal and gene abnormalities in non-isolated VSD (33/185) was significantly higher than that in isolated VSD (2/59) (17.84% vs 3.39%, p = 0.006). For non-isolated VSD, the detection rate for VSD with extra-cardiac defects (10/20) was significantly higher than that in VSD with cardiac defects (9/45) (50.00% vs 20.00%, p = 0.014) and soft markers (14/116) (50.00% vs 12.07%, p < 0.001). Trisomy 21 and 22q11.2 deletion syndrome were the most common chromosomal abnormalities. Additionally, we found six gene variants might be associated with the causative genetic mechanisms of VSD. Conclusion The rational combination of karyotyping, SNP array and Trio-WES can effectively improve the detection rate of chromosomal and gene abnormalities in VSD fetuses. Ultrasound abnormalities, such as VSD with extra-cardiac defects and multiple soft markers added detection of pathogenic abnormalities.