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Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4–11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. UK Department of Health and Social Care and The Wellcome Trust.

In July 2024, bluetongue virus serotype 3 (BTV-3) was first detected in southern Belgium, marking the onset of a major epidemic wave. This study documents, for the first time in Belgium, the ability of BTV-3 to cross the placental barrier in cattle, causing abortions and congenital central nervous system malformations. Abortion cases from January to December 2024 were monitored through the national abortion protocol, which mandates reporting and laboratory investigation (i.e., the year of emergence and the three previous years as the baseline data set). Among 5,751 reported abortions, 903 foetuses were tested by PCR, revealing widespread BTV-3 circulation. The first malformed PCR-positive foetus was recorded in mid-August, four weeks after a sharp increase in abortion rates. Lesions such as hydranencephaly were confirmed in PCR-positive foetuses, with a malformation rate of 32.24% in affected herds from weeks 36 to 52 (i.e., 22 times higher than in previous years). Gestational stage analysis indicated that congenital lesions were most frequent following infection between 70 and 130 days of gestation. Based on the observed gross lesions and the timing of abortion, it was deduced that the earliest maternal infections likely occurred in February–March 2024, implying low-level winter BTV-3 circulation before the official detection of the epidemic wave. These findings highlight the epidemiological value of systematic abortion monitoring as an early warning system tool and highlight the inadequacy of relying solely on clinical surveillance in adult ruminants. The abrupt emergence of BTV-3 across the territory without a gradual spatial spread underscores the need for anticipatory control strategies. Strategic, multivalent vaccination campaigns and enhanced abortion surveillance are critical to mitigate similar reproductive and economic losses in future bluetongue outbreaks.

Congenital cytomegalovirus is the most frequent, yet under-recognised, infectious cause of newborn malformation in developed countries. Despite its clinical and public health importance, questions remain regarding the best diagnostic methods for identifying maternal and neonatal infection, and regarding optimal prevention and therapeutic strategies for infected mothers and neonates. The absence of guidelines impairs global efforts to decrease the effect of congenital cytomegalovirus. Data in the literature suggest that congenital cytomegalovirus infection remains a research priority, but data are yet to be translated into clinical practice. An informal International Congenital Cytomegalovirus Recommendations Group was convened in 2015 to address these questions and to provide recommendations for prevention, diagnosis, and treatment. On the basis of consensus discussions and a review of the literature, we do not support universal screening of mothers and the routine use of cytomegalovirus immunoglobulin for prophylaxis or treatment of infected mothers. However, treatment guidelines for infected neonates were recommended. Consideration must be given to universal neonatal screening for cytomegalovirus to facilitate early detection and intervention for sensorineural hearing loss and developmental delay, where appropriate. The group agreed that education and prevention strategies for mothers were beneficial, and that recommendations will need continual updating as further data become available.

Genetic variants causing loss of function in the synthesis of nicotinamide adenine dinucleotide were shown to cause congenital malformations that comprise the VACTERL association. Niacin supplementation during gestation prevented similar defects in mouse models.

Surveillance of congenital anomalies is important to identify potential teratogens. This study analysed the prevalence of 61 congenital anomaly subgroups (excluding chromosomal) in 25 population-based EUROCAT registries (1980-2012). Live births, fetal deaths and terminations of pregnancy for fetal anomaly were analysed with multilevel random-effects Poisson regression models. Seventeen anomaly subgroups had statistically significant trends from 2003-2012; 12 increasing and 5 decreasing. The annual increasing prevalence of severe congenital heart defects, single ventricle, atrioventricular septal defects and tetralogy of Fallot of 1.4% (95% CI: 0.7% to 2.0%), 4.6% (1.0% to 8.2%), 3.4% (1.3% to 5.5%) and 4.1% (2.4% to 5.7%) respectively may reflect increases in maternal obesity and diabetes (known risk factors). The increased prevalence of cystic adenomatous malformation of the lung [6.5% (3.5% to 9.4%)] and decreased prevalence of limb reduction defects [-2.8% (-4.2% to -1.5%)] are unexplained. For renal dysplasia and maternal infections, increasing trends may be explained by increased screening, and deceases in patent ductus arteriosus at term and increases in craniosynostosis, by improved follow up period after birth and improved diagnosis. For oesophageal atresia, duodenal atresia/stenosis and ano-rectal atresia/stenosis recent changes in prevalence appeared incidental when compared with larger long term fluctuations. For microcephaly and congenital hydronephrosis trends could not be interpreted due to discrepancies in diagnostic criteria. The trends for club foot and syndactyly disappeared once registries with disparate results were excluded. No decrease in neural tube defects was detected, despite efforts at prevention through folic acid supplementation.

Maternal obesity can impair embryo development and offspring health, yet the mechanisms responsible remain poorly understood. In a high-fat diet (HFD)-based female mouse model of obesity, we identified a marked reduction of Stella (also known as DPPA3 or PGC7) protein in oocytes. Starting with this clue, we found that the establishment of pronuclear epigenetic asymmetry in zygotes from obese mice was severely disrupted, inducing the accumulation of maternal 5-hydroxymethylcytosine modifications and DNA lesions. Furthermore, methylome-wide sequencing analysis detected global hypomethylation across the zygote genome in HFD-fed mice, with a specific enrichment in transposon elements and unique regions. Notably, overexpression of Stella in the oocytes of HFD-fed mice not only restored the epigenetic remodeling in zygotes but also partly ameliorated the maternal-obesity-associated developmental defects in early embryos and fetal growth. Thus, Stella insufficiency in oocytes may represent a critical mechanism that mediates the phenotypic effects of maternal obesity in embryos and offspring. The authors find that, in a high-fat diet (HFD) mouse model, levels of Stella protein are reduced in oocytes, leading to abnormal epigenetic patterning during development and to embryonic growth defects. Overexpression of Stella in oocytes from HFD-fed mice partially ameliorates developmental defects.

In this study, the risk of birth defects was increased with IVF but was no longer significant after adjustment for maternal factors. The risk of birth defects associated with intracytoplasmic sperm injection remained higher after multivariate adjustment. Residual confounding cannot be ruled out. Consistent evidence from individual studies, including registry-based cohort studies 1 , 2 and meta-analyses, has linked assisted conception involving in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) with an increased risk of birth defects. 3 – 8 The associations between the use of these techniques and birth defects have appeared to be stronger for singleton births than for multiple births. 9 , 10 It is unclear whether the excess of birth defects after IVF or ICSI may be attributable to patient characteristics related to infertility, 8 rather than to the treatment, and whether the risk is similar across assisted reproductive technologies and related therapies. 3 , 11 , . . .

Gene regulatory networks, in which differential expression of regulator genes induce differential expression of their target genes, underlie diverse biological processes such as embryonic development, organ formation and disease pathogenesis. An archetypical systems biology approach to mapping these networks involves the combined application of (1) high-throughput sequencing-based transcriptome profiling (RNA-seq) of biopsies under diverse network perturbations and (2) network inference based on gene–gene expression correlation analysis. The comparative analysis of such correlation networks across cell types or states, differential correlation network analysis, can identify specific molecular signatures and functional modules that underlie the state transition or have context-specific function. Here, we review the basic concepts of network biology and correlation network inference, and the prevailing methods for differential analysis of correlation networks. We discuss applications of gene expression network analysis in the context of embryonic development, cancer, and congenital diseases.