Prenatal Diagnosis of Fetuses with Increased Nuchal Translucency by Genome Sequencing Analysis

Choy, Kwong Wai; Wang, Huilin; Shi, Mengmeng; Chen, Jingsi; Yang, Zhenjun; Zhang, Rui; Yan, Huanchen; Wang, Yanfang; Chen, Shaoyun; Chau, Matthew Hoi Kin; Cao, Ye; Chan, Olivia Ym; Kwok, Yvonne K.; Zhu, Yuanfang; Chen, Min; Leung, Tak Yeung; Dong, Zirui

doi:10.1101/667311

Cited by 6 publications

(6 citation statements)

References 42 publications

(58 reference statements)

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“…Ultrasound scans showed a range of abnormalities including increased nuchal translucency, pleural effusion, cardiac anomaly, renal anomalies, intrauterine growth restriction, polyhydramnios, oligohydramnios and single umbilical artery. Similar antenatal presentations were also noted in the recent large case series and published case reports 8–40 . More than half of the cases were diagnosed after birth by clinical assessment and molecular testing.…”

Section: Discussionsupporting

confidence: 78%

Prenatal phenotype of Kabuki syndrome: A case series and literature review

Luk

Cheung

et al. 2021

Prenatal Diagnosis

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Objectives Kabuki syndrome (KS) is a genetic disorder characterized by intellectual disability, facial dysmorphism and congenital anomalies. We aim to investigate the prenatal features of fetuses with KS and to provide a comprehensive review of the literature on prenatal sonographic abnormalities associated with KS. Methods We retrospectively reviewed the prenatal ultrasound findings of all mothers of children with molecularly confirmed KS in Hong Kong, between 1991 and 2019. We also performed systematic review of the literature to identify studies on the prenatal findings in KS. Results We identified 11 cases with KS with detectable fetal ultrasound findings ranging from no detectable abnormalities to a variety of non‐specific findings including increased nuchal translucency, pleural effusion, cardiac anomalies, renal anomalies, intrauterine growth restriction, polyhydramnios, oligohydramnios and single umbilical artery. In combining our cases with the 77 cases published, 42 (50.6%) of them had more than one abnormal antenatal ultrasound finding. The most frequent ultrasound features observed were cardiac anomalies (49.4%), followed by polyhydramnios (28.9%), genitourinary anomalies (26.5%), single umbilical artery (15.7%), intrauterine growth restriction (14.5%) and hydrops fetalis/pleural effusion/ascites (12.0%). Conclusions These cases demonstrate the prenatal phenotypic heterogeneity associated with KS. Although the ultrasound abnormalities are non‐specific, KS should be considered in the differential diagnosis when these fetal findings following normal microarray analysis/karyotyping.

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Section: Discussionsupporting

confidence: 78%

Prenatal phenotype of Kabuki syndrome: A case series and literature review

Luk

Cheung

et al. 2021

Prenatal Diagnosis

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“…Therefore, prenatal diagnosis by CMA instead of expanded NIPS is highly recommended for high-risk pregnancies. Recently, the development of genome sequencing, including CNV sequencing and low-pass whole-genome sequencing, has shown the potential of next-generation sequencing for the detection of genome-wide variants 36,37 , including balanced rearrangements 38 and single nucleotide variants 39 , that cannot be detected by CMA. The implementation of invasive diagnostic testing by genome sequencing in high-risk pregnancies may provide even more comprehensive genetic information.…”

Section: Discussionmentioning

confidence: 99%

Clinical utility of expanded non‐invasive prenatal screening and chromosomal microarray analysis in high‐risk pregnancy

Zhu

Chen

Wang

et al. 2021

Ultrasound in Obstet & Gyne

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Objective To evaluate the utility of expanded non‐invasive prenatal screening (NIPS), compared with chromosomal microarray analysis (CMA), for the detection of chromosomal abnormalities in high‐risk pregnancies. Methods This was a multicenter retrospective study of singleton pregnancies at high risk for chromosomal abnormality. Patients who underwent expanded NIPS and CMA sequentially during pregnancy from 2015 to 2019 were included in the analysis. Pregnancies with a positive result for sex chromosome aneuploidy were excluded as the full details could not be retrieved. The utility of expanded NIPS and CMA for detection of chromosomal abnormalities in this cohort was compared by assessing the concordance between the results. Results Of the 774 included high‐risk pregnancies, 550 (71.1%) had a positive NIPS result, while a positive CMA result was detected in 308 (39.8%) cases. The rate of full or partial concordance between NIPS and CMA was 82.2%, 59.6% and 25.0% for trisomies 21, 18 and 13, respectively. For rare aneuploidies and segmental imbalances, NIPS and CMA results were fully or partially concordant in 7.5% and 33.3% of cases, respectively. Copy‐number variants < 5 Mb were detected more often by CMA, with an incidence of 7.9% (61/774) compared with 3.1% (24/774) by NIPS. A genetic aberration was detected by CMA in 1 in 17 (5.8%) high‐risk pregnancies that had a negative or non‐reportable NIPS result. Conclusion CMA allows for comprehensive detection of genome‐wide chromosomal abnormalities in high‐risk pregnancies. CMA should be offered instead of expanded NIPS for high‐risk pregnancies. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

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“…For fetuses with structural anomalies, prenatal whole exome sequencing (WES) has been successfully applied for clinical testing to facilitate genetic diagnosis, thereby enabling more accurate predictions of fetal prognosis and information on the risk of recurrence in future pregnancies 23‐25 . A recent study had also showed the feasibility of applying genome sequencing (GS) for prenatal diagnosis of fetuses with increased NT for comprehensive detection of various disease‐causing genomic variants 26 . However, accurate prenatal diagnosis of skeletal dysplasia by invasive procedures is still under debate in the absence of a relevant family history, and the time from invasive testing to diagnosis can be lengthy 12 .…”

Section: Discussionmentioning

confidence: 99%

Noninvasive prenatal sequencing for multiple Mendelian monogenic disorders among fetuses with skeletal dysplasia or increased nuchal translucency

et al. 2020

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Objectives: To evaluate the performance of noninvasive prenatal sequencing for multiple Mendelian monogenic disorders (NIPS-M) among fetuses with skeletal abnormalities or increased nuchal translucency (NT). Methods: Pregnancies with fetal skeletal abnormalities or increased NT (≥3.0 mm) observed by ultrasonography were recruited between October 2017 and March 2019. Parental blood from 13 couples were collected for NIPS-M testing reported. All the NIPS-M results were followed up by invasive diagnostic testing or neonatal examination. Results: Among the 13 cases, 8 (61.5%) yielded positive results for pathogenic variants in the FGFR3, COL1A1, RAF1, PTPN11 and SOS1 genes by NIPS-M. One case was excluded for further analysis due to insufficient fetal DNA (<4.5%). De novo mutations were reported in six of the eight positive cases (75%). The other two were inconclusive as the pathogenic variants were detected in both plasma and genomic DNA of the mothers. The sensitivity of NIPS-M was 100%. Conclusions: Our pilot study demonstrates that NIPS-M is an accurate approach for detection of multiple monogenic disorders among fetuses with skeletal abnormalities or increased NT. It serves as an alternative and highly sensitive method to provide valuable molecular information for these groups of women who are reluctant to undergo invasive procedure.

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Prenatal Diagnosis of Fetuses with Increased Nuchal Translucency by Genome Sequencing Analysis

Cited by 6 publications

References 42 publications

Prenatal phenotype of Kabuki syndrome: A case series and literature review

Prenatal phenotype of Kabuki syndrome: A case series and literature review

Clinical utility of expanded non‐invasive prenatal screening and chromosomal microarray analysis in high‐risk pregnancy

Noninvasive prenatal sequencing for multiple Mendelian monogenic disorders among fetuses with skeletal dysplasia or increased nuchal translucency

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