The routine assessment to determine the genetic etiology for fetal ultrasound anomalies follows a sequential approach, which usually takes about 6-8 weeks turnaround time (TAT). We evaluated the clinical utility of simultaneous detection of copy number variations (CNVs) and single nucleotide variants (SNVs)/small insertion-deletions (indels) in fetuses with a normal karyotype with ultrasound anomalies. We performed CNV detection by chromosomal microarray analysis (CMA) or low pass CNV-sequencing (CNV-seq), and in parallel SNVs/indels detection by trio-based clinical exome sequencing (CES) or whole exome sequencing (WES). Eight-three singleton pregnancies with a normal fetal karyotype were enrolled in this prospective observational study. Pathogenic or likely pathogenic variations were identified in 30 cases (CNVs in 3 cases, SNVs/indels in 27 cases), indicating an overall molecular diagnostic rate of 36.1% (30/83). Two cases had both a CNV of uncertain significance (VOUS) and likely pathogenic SNV, and one case carried both a VOUS CNV and an SNV. We demonstrated that simultaneous analysis of CNVs and SNVs/indels can improve the diagnostic yield of prenatal diagnosis with shortened reporting time, namely, 2-3 weeks. Due to the relatively long TAT for sequential procedure for prenatal genetic diagnosis, as well as recent sequencing technology advancements, it is clinically necessary to consider the simultaneous evaluation of CNVs and SNVs/indels to enhance the diagnostic yield and timely TAT, especially for cases in the late second trimester or third trimester.
Keywords: CMA; CNV-seq; clinical exome sequencing (CES); fetal ultrasound anomalies; prenatal diagnosis.