Simultaneous Detection of CNVs and SNVs Improves the Diagnostic Yield of Fetuses with Ultrasound Anomalies and Normal Karyotypes.

Junjie Bai,Mingming Wang,Xiya Zhou,Na Hao,Chunli Wang,Yunshu Ouyang,Hua Meng,Mengsu Xiao,Victor Wei Zhang,Zhonghui Xu,Jiazhen Chang,Juntao Liu,Yulin Jiang,Qingwei Qi,Jiangshan Guo

doi:10.3390/genes11121397

Abstract

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.

Highlights

Fetal structural abnormalities detected by ultrasound can be identified in 2% to 3% of pregnancies.A significant portion of these fetuses have an underlying genetic etiology associated with a spectrum of mutation types, including chromosome aneuploidy, copy number variations (CNVs), uniparental disomy (UPD) and single nucleotide variation (SNV)/small insertion-deletions.In general, aneuploidies are found in 8% to 10% of unselected fetuses with abnormal ultrasound results, while microdeletions/microduplications are identified in another 6% by chromosomal microarray analysis (CMA) [1]
2018-IRB-076); (2) singleton pregnancy and a fetus with at least one ultrasonic structural anomaly; (3) fetal sample was obtained through an invasive procedure, including chorionic villus sampling (CVS), amniocentesis or cordocentesis; (4) prenatal genetic diagnosis including karyotyping, CMA and trio-based clinical exome sequencing (CES) was performed in parallel; (5) all of the above-mentioned testing were performed on each prenatal sample successfully; and (6) karyotyping results were normal
The fetuses were categorized into 11 phenotypic groups based on the abnormalities in different organ systems detected by ultrasound

Summary

Introduction

Aneuploidies are found in 8% to 10% of unselected fetuses with abnormal ultrasound results, while microdeletions/microduplications are identified in another 6% by chromosomal microarray analysis (CMA) [1]. The routine procedure for prenatal genetic diagnosis of cases with fetal anomalies is a sequential procedure in most of prenatal clinics [7], namely, performing karyotyping to reveal the presence or absence of aneuploidy and higher resolution CMA to detect CNVs in fetuses with a normal karyotype. When these results were uninformative, ES was performed to detect exonic

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