University of Oulu

Czamara, D., Cruceanu, C., Lahti-Pulkkinen, M., Dieckmann, L., Ködel, M., Sauer, S., Rex-Haffner, M., Sammallahti, S., Kajantie, E., Laivuori, H., Lahti, J., Räikkönen, K., & Binder, E. B. (2022). Genome-Wide Copy Number Variant and High-Throughput Transcriptomics Analyses of Placental Tissues Underscore Persisting Child Susceptibility in At-Risk Pregnancies Cleared in Standard Genetic Testing. International Journal of Molecular Sciences, 23(19), 11448.

Genome-wide copy number variant and high-throughput transcriptomics analyses of placental tissues underscore persisting child susceptibility in at-risk pregnancies cleared in standard genetic testing

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Author: Czamara, Darina1; Cruceanu, Cristiana1,2; Lahti-Pulkkinen, Marius3,4,5;
Organizations: 1Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, 80804 Munich, Germany
2Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden
3Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland
4Finnish Institute for Health and Welfare, 00271 Helsinki, Finland
5Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
6International Max Planck Research School for Translational Psychiatry, 80804 Munich, Germany
7Department of Obstetrics and Gynaecology, Helsinki University Hospital and University of Helsinki, 00014 Helsinki, Finland
8Children’s Hospital, Helsinki University Hospital and University of Helsinki, 00014 Helsinki, Finland
9Faculty of Medicine, PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, 90014 Oulu, Finland
10Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway
11Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
12Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland
13Department of Obstetrics and Gynecology, Tampere University Hospital and Faculty of Medicine and Health Technology, Center for Child, Adolescent and Maternal Health Research, Tampere University, 33520 Tampere, Finland
14Department of Psychiatry and Behavioral Sciences, School of Medicine, Emory University, Atlanta, GA 30322, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.9 MB)
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Language: English
Published: Multidisciplinary Digital Publishing Institute, 2022
Publish Date: 2023-06-16


Several studies have shown that children from pregnancies with estimated first-trimester risk based on fetal nuchal translucency thickness and abnormal maternal serum pregnancy protein and hormone levels maintain a higher likelihood of adverse outcomes, even if initial testing for known genetic conditions is negative. We used the Finnish InTraUterine cohort (ITU), which is a comprehensively characterized perinatal cohort consisting of 943 mothers and their babies followed throughout pregnancy and 18 months postnatally, including mothers shortlisted for prenatal genetic testing but cleared for major aneuploidies (cases: n = 544, 57.7%) and control pregnancies (n = 399, 42.3%). Using genome-wide genotyping and RNA sequencing of first-trimester and term placental tissue, combined with medical information from registry data and maternal self-report data, we investigated potential negative medical outcomes and genetic susceptibility to disease and their correlates in placenta gene expression. Case mothers did not present with higher levels of depression, perceived stress, or anxiety during pregnancy. Case children were significantly diagnosed more often with congenital malformations of the circulatory system (4.12 (95% CI [1.22–13.93]) higher hazard) and presented with significantly more copy number duplications as compared to controls (burden analysis, based on all copy number variants (CNVs) with at most 10% frequency, 823 called duplications in 297 cases versus 626 called duplications in 277 controls, p = 0.01). Fifteen genes showed differential gene expression (FDR < 0.1) in association with congenital malformations in first-trimester but not term placenta. These were significantly enriched for genes associated with placental dysfunction. In spite of normal routine follow-up prenatal testing results in early pregnancy, case children presented with an increased likelihood of negative outcomes, which should prompt vigilance in follow-up during pregnancy and after birth.

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Series: International journal of molecular sciences
ISSN: 1661-6596
ISSN-E: 1422-0067
ISSN-L: 1661-6596
Volume: 23
Issue: 19
Article number: 11448
DOI: 10.3390/ijms231911448
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
3123 Gynaecology and paediatrics
Funding: The ITU is funded by the Academy of Finland (award numbers: 284859, 312670, 1324596). CC received funding from the Banting Postdoctoral Fellowship. ML-P receives funding from the Academy of Finland, University of Helsinki Funds. The funders had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Copyright information: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (