Non-invasive prenatal testing reveals copy number variations related to pregnancy complications

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Abstract

Background

Pregnancy complications could lead to maternal and fetal morbidity and mortality. Early diagnosing and managing complications have been associated with good outcomes. The placenta was an important organ for development of pregnancy complications. Thus, non-invasive prenatal testing technologies could detect genetic variations, such as aneuploidies and sub-chromosomal copy number variations, reflecting defective placenta by maternal plasma cffDNAs. Maternal cffDNAs had been proved to derive from trophoblast cells of placenta.

Results

In order to find out the relationship between genetic variations and pregnancy complications, we reviewed NIPT results for subchromosomal copy number variations in a cohort of 3890 pregnancies without complications and 441 pregnancies with pregnancy complications including gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), preterm prelabor rupture of membranes (PPROM) and placenta implantation abnormalities (PIA). For GDMs, we identified three CNV regions containing some members of alpha- and beta-defensins, such as DEFA1, DEFA3, DEFB1. For PIHs, we found three duplication and one deletion region including Pcdhα, Pcdhβ, and Pcdhγ, known as protocadherins, which were complicated by hypertensive disorders. For PPROMs and PIAs, we identified one and two CNV regions, respectively. SFTPA2, SFTPD and SFTPA1, belonging to surfactant protein, was considered to moderated the inflammatory activation within the fetal extra-embryonic compartment, associated to duration of preterm prelabor rupture of fetal membranes, while MEF2C and TM6SF1 could be involved in trophoblast invasion and differentiation.

Conclusions

Our findings gave a clue to correlation between genetic variations of maternal cell-free DNAs and pregnancy complications.

Electronic supplementary material

The online version of this article (10.1186/s13039-019-0451-3) contains supplementary material, which is available to authorized users.

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Most cited references 45

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Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes.

Daniel B DiGiulio, Roberto Romero, Juan Pedro Kusanovic … (2010)

The role played by microbial invasion of the amniotic cavity (MIAC) in preterm pre-labor rupture of membranes (pPROM) is inadequately characterized, in part because of reliance on cultivation-based methods. Amniotic fluid from 204 subjects with pPROM was analyzed with both cultivation and molecular methods in a retrospective cohort study. Broad-range and group-specific polymerase chain reaction (PCR) assays targeted small subunit ribosomal DNA (rDNA), or other gene sequences, from bacteria, fungi, and archaea. Results were correlated with measurements of host inflammation, as well as pregnancy and perinatal outcomes. The prevalence of MIAC was 34% (70/204) by culture, 45% (92/204) by PCR, and 50% (101/204) by both methods combined. The number of bacterial species revealed by PCR (44 species-level phylotypes) was greater than that by culture (14 species) and included as-yet uncultivated taxa. Some taxa detected by PCR have been previously associated with the gastrointestinal tract (e.g., Coprobacillus sp.), the mouth (e.g., Rothia dentocariosa), or the vagina in the setting of bacterial vaginosis (e.g., Atopobium vaginae). The relative risk for histologic chorioamnionitis was 2.1 for a positive PCR [95% confidence interval (CI), 1.4-3.0] and 2.0 for a positive culture (95% CI, 1.4-2.7). Bacterial rDNA abundance exhibited a dose relationship with gestational age at delivery (R(2) = 0.26; P < 0.01). A positive PCR was associated with lower mean birthweight, and with higher rates of respiratory distress syndrome and necrotizing enterocolitis (P < 0.05 for each outcome). MIAC in pPROM is more common than previously recognized and is associated in some cases with uncultivated taxa, some of which are typically associated with the gastrointestinal tract. The detection of MIAC by molecular methods has clinical significance.

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Human beta-defensins.

Lee-Jane Lu, M Pazgier, Kuender D. Yang … (2006)

The last decade led to the discovery and characterization of several human beta-defensins. Analysis of genomic information indicates that the number of beta-defensin-like molecules encoded by the human genome may number in the tens. Growing interest in beta-defensins steadily enhances our knowledge about various aspects of their gene location, expression patterns and the transcription factors involved in their regulation in vivo. The hallmark property of beta-defensins, their antimicrobial activity, is clearly only the tip of the iceberg in the extensive network of inter-relations within the immune system in which these peptides function. Structural studies of beta-defensins provide the molecular basis for a better understanding of their properties, functions and their potential for practical applications. In this review, we present some recent advances in the studies of human beta-defensins, with an emphasis on possible correlations between their structural and functional properties.

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Increased risk of ischemic heart disease, hypertension, and type 2 diabetes in women with previous gestational diabetes mellitus, a target group in general practice for preventive interventions: A population-based cohort study

Barbara Daly, Konstantinos Toulis, Neil Thomas … (2018)

Background Gestational diabetes mellitus (GDM) is associated with developing type 2 diabetes, but very few studies have examined its effect on developing cardiovascular disease. Methods and findings We conducted a retrospective cohort study utilizing a large primary care database in the United Kingdom. From 1 February 1990 to 15 May 2016, 9,118 women diagnosed with GDM were identified and randomly matched with 37,281 control women by age and timing of pregnancy (up to 3 months). Adjusted incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were calculated for cardiovascular risk factors and cardiovascular disease. Women with GDM were more likely to develop type 2 diabetes (IRR = 21.96; 95% CI 18.31–26.34) and hypertension (IRR = 1.85; 95% CI 1.59–2.16) after adjusting for age, Townsend (deprivation) quintile, body mass index, and smoking. For ischemic heart disease (IHD), the IRR was 2.78 (95% CI 1.37–5.66), and for cerebrovascular disease 0.95 (95% CI 0.51–1.77; p-value = 0.87), after adjusting for the above covariates and lipid-lowering medication and hypertension at baseline. Follow-up screening for type 2 diabetes and cardiovascular risk factors was poor. Limitations include potential selective documentation of severe GDM for women in primary care, higher surveillance for outcomes in women diagnosed with GDM than control women, and a short median follow-up postpartum period, with a small number of outcomes for IHD and cerebrovascular disease. Conclusions Women diagnosed with GDM were at very high risk of developing type 2 diabetes and had a significantly increased incidence of hypertension and IHD. Identifying this group of women in general practice and targeting cardiovascular risk factors could improve long-term outcomes.

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Author and article information

Contributors

Hailiang Liu:

ORCID: http://orcid.org/0000-0002-4364-2826

86-769-22893126 , hlliu@capitalbiotech.com

Hongbo Qi: +86 023 89011101 , qihongbocy@gmail.com

Journal

Journal ID (nlm-ta): Mol Cytogenet

Journal ID (iso-abbrev): Mol Cytogenet

Title: Molecular Cytogenetics

Publisher: BioMed Central (London )

ISSN (Electronic): 1755-8166

Publication date (Electronic): 30 August 2019

Publication date PMC-release: 30 August 2019

Publication date Collection: 2019

Volume: 12

Electronic Location Identifier: 38

Affiliations

[1 ]GRID grid.452206.7, Department of Obstetrics, , The First Affiliated Hospital of Chongqing Medical University, ; Chongqing, 400016 People’s Republic of China

[2 ]ISNI 0000 0000 8653 0555, GRID grid.203458.8, State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, , Chongqing Medical University, ; Chongqing, 400016 People’s Republic of China

[3 ]ISNI 0000 0000 8653 0555, GRID grid.203458.8, International Collaborative Laboratory of Reproduction and Development of Chinese Ministry of Education, , Chongqing Medical University, ; No.1 Youyi Road, Yuzhong District, Chongqing, 400016 People’s Republic of China

[4 ]Beijing CapitalBio Medical Laboratory, Beijing, 101111 China

[5 ]CapitalBio Technology Inc., Beijing, 101111 China

[6 ]ISNI 0000 0000 8877 7471, GRID grid.284723.8, Department of Medical Genetics, , School of Basic Medical Sciences, Southern Medical University, ; Guangzhou, 510515 Guangdong China

Author information

Hailiang Liu http://orcid.org/0000-0002-4364-2826

Article

Publisher ID: 451

DOI: 10.1186/s13039-019-0451-3

PMC ID: 6716937

SO-VID: 9dc8c2a2-6758-4819-9a95-d4ae0ec78291

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 18 July 2019

Date accepted : 21 August 2019

Funding

Funded by: The National Key Research and Development Program of Reproductive Health & Major Birth Defects Control and Prevention

Award ID: No.2016YFC1000407

Funded by: Key Program of International Cooperation of NSFC

Award ID: No. 81520108013

Funded by: National Natural Science Foundation of China for Youth

Award ID: No. 31501207

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: noninvasive prenatal testing (nipt),copy number variation (cnv),gestational diabetes mellitus (gdm),pregnancy-induced hypertension (pih),preterm prelabor rupture of membranes (pprom),placenta implantation abnormalities (pia)

Data availability:

ScienceOpen disciplines: Genetics

Keywords: noninvasive prenatal testing (nipt), copy number variation (cnv), gestational diabetes mellitus (gdm), pregnancy-induced hypertension (pih), preterm prelabor rupture of membranes (pprom), placenta implantation abnormalities (pia)

Non-invasive prenatal testing reveals copy number variations related to pregnancy complications

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Most cited references 45

Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes.

Human beta-defensins.

Increased risk of ischemic heart disease, hypertension, and type 2 diabetes in women with previous gestational diabetes mellitus, a target group in general practice for preventive interventions: A population-based cohort study

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