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Clinical application of chromosomal microarray analysis in fetuses with increased nuchal translucency and normal karyotype.

ABSTRACT: BACKGROUND:Submicroscopic chromosomal imbalance is associated with an increased nuchal translucency (NT). Most previous research has recommended the use of chromosomal microarray analysis (CMA) for prenatal diagnosis if the NT ? 3.5 mm. However, there is no current global consensus on the cutoff value for CMA. In this study, we aimed to discuss the fetuses with smaller increased NT which was between cutoff value of NT for karyotype analysis (NT of 2.5 mm in China) and the recommended cutoff value for CMA (NT of 3.5 mm) whether should be excluded from CMA test. METHODS:Singleton pregnant women (N = 192) who had undergone invasive procedures owing to an increased NT (NT ? 2.5 mm) were enrolled. Fetal cells were collected and subjected to single nucleotide polymorphism array and karyotype analyses simultaneously. Cases were excluded if the karyotype analysis indicated aneuploidy and apparent structural aberrations. RESULTS:Fourteen cases of aneuploidy and four cases of structural abnormalities were excluded. Of the remaining 174 cases, 119 fetuses had NTs of 2.5-3.4 mm, and 55 fetuses with NT ? 3.5 mm. Eleven copy number variants (CNVs) were identified. In fetuses with smaller NTs, six (6/119, 5.9%) variations were detected, including two (2/119, 1.6%) clinically significant CNVs (pathogenic or likely pathogenic CNV), one likely benign CNV, two variants unknown significance, and one incidental CNV. Five (5/55, 9.1%) variations were found in fetuses with NT ? 3.5 mm. Among these CNVs, three (3/55, 5.5%) cases had clinically significant CNVs, and two had likely benign CNV. There were no statistically significant differences in the incidence of all CNVs and clinically significant CNVs in the two groups (p > 0.05). CONCLUSION:CMA improved the diagnostic yield of chromosomal aberrations for fetuses with NTs of 2.5-3.4 mm and apparently normal karyotype, regardless of whether other ultrasonic abnormalities were observed.

SUBMITTER: Su L

PROVIDER: S-EPMC6687862 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Clinical application of chromosomal microarray analysis in fetuses with increased nuchal translucency and normal karyotype.

Su Linjuan L Huang Hailong H An Gang G Cai Meiying M Wu Xiaoqing X Li Ying Y Xie Xiaorui X Lin Yuan Y Wang Meiying M Xu Liangpu L

Molecular genetics & genomic medicine 20190617 8

<h4>Background</h4>Submicroscopic chromosomal imbalance is associated with an increased nuchal translucency (NT). Most previous research has recommended the use of chromosomal microarray analysis (CMA) for prenatal diagnosis if the NT ≥ 3.5 mm. However, there is no current global consensus on the cutoff value for CMA. In this study, we aimed to discuss the fetuses with smaller increased NT which was between cutoff value of NT for karyotype analysis (NT of 2.5 mm in China) and the recommended cut ...[more]

PMID: 31209990

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Project description:ObjectivesIncreased nuchal translucency (NT) thickness is an antenatal marker of aneuploidy or malformation that can lead to termination of pregnancy. This study assessed the long-term neurodevelopmental prognosis of infants who had isolated increased NT in utero.MethodsThis was a prospective cohort study of infants with a NT thickness > 95th percentile in the first trimester, but with a normal karyotype and no major anomalies, and controls with normal NT matched for birth weight, Apgar score, place of birth, parity and gestational age at birth. At 2 years of corrected age, all infants underwent the psychometric Brunet-Lézine test to evaluate their developmental quotient (DQ), overall (global) and specifically for the areas of posture, language, coordination and sociability.ResultsA total of 203 chromosomally normal infants were included in the increased-NT group and 208 in the control group. The mean global DQ was significantly lower in the increased-NT group than in the control group (108.6 ± 9.7 vs 112.8 ± 8.3; P < 0.0001), but it was within the normal range expected for that age in both groups. Similarly, the mean DQs for coordination, sociability and language, but not for posture, were significantly lower in infants with increased NT than in controls. Only one case with increased NT had a DQ < 70 (defined as severe neurodevelopmental impairment), compared with none in the control group. The difference between the two groups remained significant for a NT threshold ≥ 99th percentile and when the data were adjusted for NT thickness, the infant's sex and the mother's educational level. In the increased-NT group, NT thickness was < 3.5 mm in over half (56%) of the infants, between 3.5 mm and 5 mm in 33% and > 5 mm in 11%, with a mean global DQ of 108.4, 110.1 and 109.7, respectively.ConclusionsInfants who had isolated increased fetal NT in the first trimester had a significantly lower, but normal, DQ at a corrected age of 2 years, when compared with controls. The findings were independent of the infant's sex, fetal NT thickness and the mother's educational level. © 2020 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Project description:Background: Increased nuchal translucency (NT) is an important biomarker associated with increased risk of fetal structural anomalies. It is known to be contributed by a wide range of genetic etiologies from single-nucleotide variants to those affecting millions of base pairs. Currently, prenatal diagnosis is routinely performed by karyotyping and chromosomal microarray analysis (CMA); however, both of them have limited resolution. The diversity of the genetic etiologies warrants an integrated assay such as genome sequencing (GS) for comprehensive detection of genomic variants. Herein, we aim to evaluate the feasibility of applying GS in prenatal diagnosis for the fetuses with increased NT. Methods: We retrospectively applied GS (> 30-fold) for fetuses with increased NT (?3.5?mm) who underwent routine prenatal diagnosis. Detection of single-nucleotide variants, copy number variants, and structural rearrangements was performed simultaneously, and the results were integrated for interpretation in accordance with the guidelines of the American College of Medical Genetics and Genomics. Pathogenic or likely pathogenic (P/LP) variants were selected for validation and parental confirmation, when available. Results: Overall, 50 fetuses were enrolled, including 34 cases with isolated increased NT and 16 cases with other fetal structural malformations. Routine CMA and karyotyping reported eight P/LP CNVs, yielding a diagnostic rate of 16.0% (8/50). In comparison, GS provided a twofold increase in diagnostic yield (32.0%, 16/50), including one mosaic turner syndrome, eight cases with microdeletions/microduplications, and seven cases with P/LP point mutations. Moreover, GS identified two cryptic insertions and two inversions. Follow-up study further demonstrated the potential pathogenicity of an apparently balanced insertion that disrupted an OMIM autosomal dominant disease-causing gene at the insertion site. Conclusions: Our study demonstrates that applying GS in fetuses with increased NT can comprehensively detect and delineate the various genomic variants that are causative to the diseases. Importantly, prenatal diagnosis by GS doubled the diagnostic yield compared with routine protocols. Given a comparable turnaround time and less DNA required, our study provides strong evidence to facilitate GS in prenatal diagnosis, particularly in fetuses with increased NT.

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Clinical application of chromosomal microarray analysis in fetuses with increased nuchal translucency and normal karyotype.

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Clinical application of chromosomal microarray analysis in fetuses with increased nuchal translucency and normal karyotype.

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