Clinical efficiency of simultaneous CNV-seq and whole-exome sequencing for testing fetal structural anomalies

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Abstract
Background: Birth defects are responsible for approximately 7% of neonatal deaths worldwide by World Health Organization in 2004. Many methods have been utilized for examining the congenital anomalies in fetuses. This study aims to investigate the efficiency of simultaneous CNV-seq and whole-exome sequencing (WES) in the diagnosis of fetal anomaly based on a large Chinese cohort. Methods: In this cohort study, 1800 pregnant women with singleton fetus in Hubei Province were recruited from 2018 to 2020 for prenatal ultrasonic screening. Those with fetal structural anomalies were transferred to the Maternal and Child Health Hospital of Hubei Province through a referral network in Hubei, China. After multidisciplinary consultation and decision on fetal outcome, products of conception (POC) samples were obtained. Simultaneous CNV-seq and WES was conducted to identify the fetal anomalies that can compress initial DNA and turnaround time of reports. Results: In total, 959 couples were finally eligible for the enrollment. A total of 227 trios were identified with a causative alteration (CNV or variant), among which 191 (84.14%) were de novo. Double diagnosis of pathogenic CNVs and variants have been identified in 10 fetuses. The diagnostic yield of multisystem anomalies was significantly higher than single system anomalies (32.28% vs. 22.36%, P = 0.0183). The diagnostic rate of fetuses with consistent intra- and extra-uterine phenotypes (172/684) was significantly higher than the rate of these with inconsistent phenotypes (17/116, P = 0.0130). Conclusions: Simultaneous CNV-seq and WES analysis contributed to fetal anomaly diagnosis and played a vital role in elucidating complex anomalies with compound causes.
Funding Information
  • CAMS Innovation Fund for Medical Sciences (2020-I2M-C, T-B-046)
  • National Key R&D Program of China (2019YFC1005105)
  • Hubei Province health and family planning scientific research project (WJ2018H0132, WJ2017Z019)
  • Hubei Province Natural Science Foundation (2020CFB164)
  • Key R&D Program of Hubei Science and Technology Department (2020BCB002)
  • Key Program of Hubei Science and Technology Department aiding Xinjiang and Tibet Province (2018AKB1496)

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