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Metabolomics Analysis of Amniotic Fluid in Euploid Foetuses with Thickened Nuchal Translucency by Gas Chromatography-Mass Spectrometry.

ABSTRACT: Persistence of a fetal thickened nuchal translucency (NT), one of the most sensitive and specific individual markers of fetal disorders, is strongly correlated with the possibility of a genetic syndrome, congenital infections, or other malformations. Thickened NT can also be found in normal pregnancies. Several of its pathophysiological aspects still remain unexplained. Metabolomics could offer a fresh opportunity to explore maternal-foetal metabolism in an effort to explain its physiological and pathological mechanisms. For this prospective case-control pilot study, thirty-nine samples of amniotic fluids were collected, divisible into 12 euploid foetuses with an enlarged nuchal translucency (>NT) and 27 controls (C). Samples were analyzed using gas chromatography mass spectrometry. Multivariate and univariate statistical analyses were performed to find a specific metabolic pattern of >NT class. The correlation between the metabolic profile and clinical parameters was evaluated (NT showed an R² = 0.75, foetal crown-rump length showed R² = 0.65, pregnancy associated plasma protein-A showed R² = 0.60). Nine metabolites significantly differing between >NT foetuses and C were detected: 2-hydroxybutyric acid, 3-hydroxybutyric, 1,5 Anydro-Sorbitol, cholesterol, erythronic acid, fructose, malic acid, threitol, and threonine, which were linked to altered pathways involved in altered energetic pathways. Through the metabolomics approach, it was possible to identify a specific metabolic fingerprint of the fetuses with >NT.

SUBMITTER: Murgia F

PROVIDER: S-EPMC8466859 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

Project description:BACKGROUND:Microcephaly has become a major public health problem in Brazil. The total number of newborns with microcephaly was reported to be >4000 in June 2016. Studies suggest that Zika Virus is a major cause of new microcephaly cases in Brazil. Inside the uterus, the foetus is surrounded by the Amniotic Fluid, a proximal fluid that contains foetal and maternal cells as well as microorganisms and where Zika Virus was already found. CASE PRESENTATION:A previous study reported the presence of the Zika Virus in the amniotic fluid (collected in the 28th gestational week) of two pregnant women carrying microcephaly foetuses in Brazil. The virus was detected by means of real-time PCR and metatranscriptomic analysis. We compared the microbiome of these two cases with metatranscriptomic sequences from 16 pregnant women collected at various times in their pregnancies CONCLUSION: Several strains of bacteria (e.g., Streptococcus and Propionibacterium) found in Amniotic Fluid may be involved in neurological diseases. When the foetus is infected by the Zika Virus, due to neurological damage, they do not move inside the uterus, thus changing the Amniotic Fluid environment, potentially leading to secondary problems. Zika infection could also lead to an immunodeficient state, making bacterial colonization of the foetuses easier. An altered microbial composition during pregnancy may also result in harmful secondary metabolite production from certain microbes that further impair foetal brain development. However, these observations of potentially harmful microbial species are correlations and thus cannot be assumed to be causative agents of (microcephaly) disease. In our study, microbial and parasitic diversity of the Amniotic Fluid was lower in patients infected by ZIKV, compared to that of Prenatal and Preterm controls. The present study was a first attempt to shed light on the microbial and parasitic diversity associated with ZIKV-infected pregnant women bearing microcephaly foetuses, and the presence of diverse microbial and parasite communities in the Amniotic Fluid suggests a poor health status of both the pregnant women and the foetuses they carry.

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Metabolomics Analysis of Amniotic Fluid in Euploid Foetuses with Thickened Nuchal Translucency by Gas Chromatography-Mass Spectrometry.

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