Combined application of CNV-seq and whole-exome sequencing for testing fetal abnormalities:a retrospective analysis

Background: Birth defects have complex and diverse causes, which have a profound impact on children, families and society. Genetic factors are an important cause of birth defects. Genetic testing of fetal with abnormal intrauterine development is an effective way to reduce the risk of birth defects. Methods: Genetic testing were conducted on 154 pregnancies with fetuses exhibiting structural anomalies or ultrasound soft markers during the 10-31 weeks of pregnancy through combined of CNV-seq and whole-exome sequencing. Results: Overall positive diagnostic rates for CNV-seq and WES was 15.58% (24/154). The positive diagnostic rate for fetal structural abnormalities was 20.75% (22/106), and the rate for ultrasound soft markers was 4.17% (2/48). In the cohort of 154 cases, 13 (8.4%) fetuses had chromosomal abnormalities, including 8 (5.19%) cases of aneuploidy and 5 (3.25%) cases of copy number variations (CNVs), while 11 (7.14%) fetuses had pathogenic gene variants. Aneuploidy related diseases were Turner syndrome (3/154, 1.9%), Edwards Syndrome (3/154, 1.9%), Down Syndrome (1/154, 0.65%) and Trisomy 8 mosaicism syndrome (1/154, 0.65%1). Three CNVs (1q21.1q21.2dup, 17p11.2dup, Xq27.2q28dup) were in status of de novo, while the other two (1q21.1q21.2del, 15q11.2del) were inherited from the healthy mother. 9 variants in de novo status accounted for 81.8% (9/11) positive findings, while the other two were inherited. The most frequently occurring gene was TSC2 , followed by NSD2 , BICRA , FOXC2 , JAG1 , NFIA , SALL1 and TSC1 gene. Conclusions : The combined application of CNV-seq and WES technologies increases the positive detection rate, provides richer and more comprehensive genetic information for clinical decision-making, also shorten the duration of prenatal diagnosis. The combined testing program is a very clinically beneficial measure.