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Prenatal Diagnosis of Fetuses with Increased Nuchal Translucency By bioRxiv preprint doi: https://doi.org/10.1101/667311; this version posted June 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Prenatal Diagnosis of Fetuses with Increased Nuchal 2 Translucency by Genome Sequencing Analysis 3 4 1 bioRxiv preprint doi: https://doi.org/10.1101/667311; this version posted June 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Prenatal Diagnosis of Fetuses with Increased Nuchal 2 Translucency by Genome Sequencing Analysis 3 Kwong Wai Choy,1,2,3# Huilin Wang,4# Mengmeng Shi,1# Jingsi Chen,5# Zhenjun Yang,1 4 Rui Zhang,4 Huanchen Yan,5 Yanfang Wang,4 Shaoyun Chen,4 Matthew Hoi Kin Chau,1 5 Ye Cao,1,6 Olivia YM Chan,1 Yvonne K Kwok,1 Yuanfang Zhu,4 Min Chen,5 Tak Yeung 6 Leung,1,2,3 Zirui Dong1,2,5* 7 1. Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, 8 Hong Kong, China 9 2. Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, 10 China 11 3. The Chinese University of Hong Kong-Baylor College of Medicine Joint Center 12 for Medical Genetics, Hong Kong, China 13 4. Department of Central Laboratory, Bao'an Maternity and Child Healthcare 14 Hospital Affiliated to Jinan University School of Medicine, Key Laboratory of Birth 15 Defects Research, Birth Defects Prevention Research and Transformation Team, 16 Shenzhen, China 17 5. Department of Obstetrics and Gynecology, Key Laboratory of Reproduction and 18 Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of 19 Guangzhou Medical University, Guangzhou, Guangdong, China 20 6. Department of Molecular and Cellular Biology, Baylor College of Medicine 21 Houston, Texas, USA 22 #These authors contributed equally. 2 bioRxiv preprint doi: https://doi.org/10.1101/667311; this version posted June 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 *Email addresses for correspondence: [email protected] 3 bioRxiv preprint doi: https://doi.org/10.1101/667311; this version posted June 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Abstract 2 Background: 3 Increased Nuchal Translucency (NT) is an important biomarker associated with increased 4 risk of fetal structural anomalies. It is known to be contributed by a wide range of genetic 5 etiologies from single nucleotide variants to those affecting millions of base-pairs. 6 Currently, prenatal diagnosis is routinely performed by karyotyping and chromosomal 7 microarray analysis (CMA), however, both of them have limited resolution. The diversity 8 of the genetic etiologies warrants an integrated assay such as genome sequencing (GS) 9 for comprehensive detection of genomic variants. Herein, we aim to evaluate the 10 feasibility of applying GS in prenatal diagnosis for the fetuses with increased NT. 11 Methods: 12 We retrospectively applied GS (>30-fold) for fetuses with increased NT (≥3.5-mm), who 13 underwent routine prenatal diagnosis. Detection of single-nucleotide variants, copy- 14 number variants and structural rearrangements was performed simultaneously and the 15 results were integrated for interpretation in accordance with the guidelines of the 16 American College of Medical Genetics and Genomics. Pathogenic or likely pathogenic 17 (P/LP) variants were selected for validation and parental confirmation, when available. 18 Results: 19 Overall, 50 fetuses were enrolled, including 34 cases with isolated increased NT and 16 20 cases with other fetal structural malformations. Routine CMA and karyotyping reported 21 eight P/LP CNVs, yielding a diagnostic rate of 16.0% (8/50). In comparison, GS 22 provided a 2-fold increase in diagnostic yield (32.0%, 16/50), including one mosaic 4 bioRxiv preprint doi: https://doi.org/10.1101/667311; this version posted June 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 turner syndrome, eight cases with microdeletions/microduplications and seven cases with 2 P/LP point mutations. Moreover, GS identified two cryptic insertions and two inversions. 3 Follow-up study further demonstrated the potential pathogenicity of an apparently 4 balanced insertion which disrupted an OMIM autosomal dominant disease-causing gene 5 at the inserted site. 6 Conclusions: 7 Our study demonstrates that applying GS in fetuses with increased NT can 8 comprehensively detect and delineate the various genomic variants that are causative to 9 the diseases. Importantly, prenatal diagnosis by GS doubled the diagnostic yield 10 compared with routine protocols. Given a comparable turn-around-time and less DNA 11 required, our study provides strong evidence to facilitate GS in prenatal diagnosis, 12 particularly in fetuses with increased NT. 13 14 Keywords: 15 Increased Nuchal Translucency; Genome Sequencing; Prenatal Diagnosis; Genomic 16 Variants; Structural Rearrangement 17 18 5 bioRxiv preprint doi: https://doi.org/10.1101/667311; this version posted June 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Introduction 2 Detection of fetuses with increased nuchal translucency (NT) in routine first-trimester 3 ultrasound screening has been widely used as a sensitive indication for fetal chromosomal 4 abnormalities and/or fetal structural anomalies, such as congenital heart disorders or 5 neurodevelopmental anomalies detected in later gestations (Leung et al., 2011;Huang et 6 al., 2014;Socolov et al., 2017;Sinajon et al., 2019). Fetuses with increased NT and 7 structural malformations are frequently contributed by genetic abnormalities and have 8 poor prognoses. However, more than 80% of such cases do not obtain a causative result 9 with the current routine prenatal diagnostic tests (Leung et al., 2011;Huang et al., 10 2014;Yang et al., 2017;Sinajon et al., 2019), challenging genetic counseling and clinical 11 management. In addition, pathogenic copy-number variants (CNVs) only account for 0.8 12 to 5.3% of these fetuses with isolated increased NT (with/without other soft markers) 13 (Leung et al., 2011;Huang et al., 2014), and part of these cases would also have poor 14 outcomes. Therefore, a test for the comprehensive detection of disease associated 15 genomic variants including numerical disorders, structural rearrangements, CNVs and 16 point mutations in this prenatal cohort is warranted. 17 In prenatal diagnosis, quantitative fluorescent PCR (QF-PCR) is routinely conducted 18 for the detection of maternal cell contamination (MCC) and common aneuploidy [such as 19 Trisomy 21 (Choy et al., 2014;Sinajon et al., 2019)]. In addition, since 2010, 20 chromosomal microarray analysis (CMA) has been recommended as the first-tier test for 21 high-risk pregnancies in identification of microscopic or submicroscopic CNVs (Leung et 22 al., 2011;Huang et al., 2014;Sinajon et al., 2019). However, this approach is limited by its 23 resolution and it cannot detect single nucleotide variants (SNVs) and small 6 bioRxiv preprint doi: https://doi.org/10.1101/667311; this version posted June 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 insertions/deletions (InDels). Owing to the breakthrough of molecular technologies such 2 as next-generation sequencing and its reduction of costs over the years, whole-exome 3 sequencing (or exome sequencing, WES) has been applied for both research purposes and 4 clinical use (Drury et al., 2015;Fu et al., 2018;Leung et al., 2018;Normand et al., 5 2018;Lord et al., 2019;Petrovski et al., 2019). Emerging studies show WES has the 6 ability to provide genetic diagnoses ranging from 9.1% to 32% for the fetuses with a 7 structural anomaly (Drury et al., 2015;Fu et al., 2018;Leung et al., 2018;Normand et al., 8 2018;Lord et al., 2019;Petrovski et al., 2019), while among these cases, WES yielded 9 diagnoses in 3.2% to 21% of the fetuses with increased NT with/without structural 10 malformations (Drury et al., 2015;Lord et al., 2019;Petrovski et al., 2019). However, 11 most of these studies were conducted on prenatal cohorts after the exclusion of abnormal 12 karyotypes and/or CMA results attributed to the cost and the limited ability of WES in 13 CNV detection (Belkadi et al., 2015). These studies show the clinical utility of WES and 14 CMA in prenatal diagnosis and warrants a combination of these two approaches for each 15 case. Meanwhile, both WES and CMA are unable to detect apparently balanced structural 16 rearrangements (or structural variants, SVs), a common limitation of the current methods 17 but some of these rearrangements have been demonstrated to be disease-causing 18 (Talkowski et al., 2012a). The wide spectrum of genetic etiologies in fetuses with 19 increased NT ranging from single-base mutations to those affecting millions of base-pairs 20 and numerical disorders, warrants a holistic approach for comprehensive detection of the 21 disease-causing genetic variants. 22 Our previous studies have demonstrated the feasibility and potential diagnostic utility 23 of applying low-pass whole-genome sequencing (or genome sequencing, GS) analysis in 7 bioRxiv preprint doi: https://doi.org/10.1101/667311; this version posted June 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.
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