Evidence for uteroplacental malperfusion in fetuses with major congenital heart defects.
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ABSTRACT:
SUBMITTER: Binder J
PROVIDER: S-EPMC7001956 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeCongenital heart defects (CHD) are associated with genetic syndromes. Rapid aneuploidy testing and chromosome microarray analysis (CMA) are standard care in fetal CHD. Many genetic syndromes remain undetected with these tests. This cohort study aims to estimate the frequency of causal genetic variants, in particular structural chromosome abnormalities and sequence variants, in fetuses with severe CHD at mid-gestation, to aid prenatal counselling.MethodsFetuses with severe CHD were extracted from the PRECOR registry (2012-2016). We evaluated pre- and postnatal genetic testing results retrospectively to estimate the frequency of genetic diagnoses in general, as well as for specific CHDs.Results919 fetuses with severe CHD were identified. After exclusion of 211 cases with aneuploidy, a genetic diagnosis was found in 15.7% (111/708). These comprised copy number variants in 9.9% (70/708). In 4.5% (41/708) sequence variants were found that would have remained undetected with CMA. Interrupted aortic arch, pulmonary atresia with ventricular septal defect and atrioventricular septal defect were most commonly associated with a genetic diagnosis.ConclusionIn case of normal CMA results, parents should be offered exome sequencing sequentially, if time allows for it, especially if the CHD is accompanied by other structural malformations due to the large variety in genetic syndromes.
| S-EPMC7332415 | biostudies-literature
Project description:ObjectiveTo evaluate the feasibility of 9. 4-T postmortem MRI (pm-MRI) for assessment of major congenital heart defects (CHD) cases terminated in the early stage of gestation.MethodsFetuses with CHD detected by the detailed first-trimester ultrasound scan and terminated before 18 gestational weeks were recruited between January 2018 and June 2020. All fetuses were offered 9.4-T pm-MRI examinations and those terminated over 13+6 weeks were offered conventional autopsies simultaneously. Findings of pm-MRI were compared with those of conventional autopsy and prenatal ultrasound.ResultsA total of 19 fetuses with major CHD were analyzed, including 6 cases of the atrioventricular septal defect, 5 cases of Tetralogy of Fallot, 3 cases of hypoplastic left heart syndrome, 1 case of tricuspid atresia, 1 case of transposition of the great arteries, 1 case of severe tricuspid regurgitation, and 2 cases of complex CHD. Pm-MRI had concordant findings in 73.7% (14/19) cases, discordant findings in 15.8% (3/19) cases, and additional findings in 10.5% (2/19) cases when compared with prenatal ultrasound. Pm-MRI findings were concordant with autopsy in all 8 CHD cases terminated over 13+6 weeks.ConclusionIt is feasible to exhibit the structure of fetal heart terminated in the first trimester clearly on 9.4-T pm-MRI with an optimized scanning protocol. High-field pm-MRI could provide medical imaging information of CHD for those terminated in the early stage of gestation, especially for those limited by conventional autopsy.
| S-EPMC8830519 | biostudies-literature
Project description:BackgroundCongenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.MethodsWe used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples.ResultsWe found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples.ConclusionsA sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.
| S-EPMC10559462 | biostudies-literature
Project description:BackgroundCongenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS) but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.MethodsWe used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: 1) 45 DS-CHD (27 female, 18 male) and 2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD vs DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS vs typical development (TD) WGBS NDBS samples.ResultsWe found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3,938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS vs TD samples.ConclusionsA sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.
| S-EPMC10187438 | biostudies-literature
Project description:BackgroundThe contribution of genetic variants to congenital heart defects (CHDs) has been investigated in many postnatal cohorts but described in few prenatal fetus cohorts. Overall, specific genetic variants especially copy number variants (CNVs) leading to CHDs are somewhat diverse among different prenatal cohort studies. In this study, a total of 1118 fetuses with confirmed CHDs were recruited from three units over a 5-year period, composing 961 of singleton pregnancies and 157 of twin pregnancies. We performed chromosomal microarray analysis on all cases to detect numerical chromosomal abnormalities (NCAs) and pathogenic/likely pathogenic CNVs (P/LP CNVs) and employed whole-exome sequencing for some cases without NCAs and P/LP CNVs to detect P/LP sequence variants (P/LP SVs).ResultsOverall, NCAs and P/LP CNVs were identified in 17.6% (197/1118) of cases, with NCA accounting for 9.1% (102/1118) and P/LP CNV for 8.5% (95/1118). Nonisolated CHDs showed a significantly higher frequency of NCA than isolated CHD (27.3% vs. 4.4%, p < 0.001), but there was no significant difference in the frequency of P/LP CNVs between isolated and nonisolated CHD (11.7% vs. 7.7%). A total of 109 P/LP CNVs were identified in 95 fetuses, consisting of 97 (89.0%) de novo, 6 (5.5%) parental inherited and 6 (5.5%) with unavailable parental information. The 16p11.2 proximal BP4-BP5 deletion was detected in 0.9% (10/1118) of all cases, second only to the most common 22q11.21 proximal A-D deletion (2.1%, 23/1118). Most of the 16p11.2 deletions (8/10) detected were de novo, and were enriched in CHD cases compared with a control cohort from a previous study. Additionally, SV was identified in 12.9% (8/62) of cases without NCA and P/LP CNV, most of which were de novo with autosomal dominant inheritance.ConclusionsOur cohort study provides a deep profile of the contribution of genetic variants to CHDs in both singleton and twin fetuses; NCA and P/LP CNV contribute to 9.1% and 8.5% of CHD in fetuses, respectively. We confirmed the 16p11.2 deletion as a CHD-associated hotspot CNV, second only to the 22q11.21 deletion in frequency. Most 16p11.2 deletions detected were de novo. Additionally, P/LP SV was identified in 12.9% (8/62) of fetuses without NCA or P/LP CNV.
| S-EPMC10768341 | biostudies-literature
Project description:Background and objectivesCongenital heart defect (CHD) is one of the most common birth defects. The aim of this cohort study was to evaluate the prevalence of chromosomal abnormalities and the clinical utility of chromosomal microarray analysis (CMA) in fetuses with different types of CHD, aiming to assist genetic counseling and clinical decision-making.MethodsIn this study, 642 fetuses with CHD were enrolled from a single center over a six-year period (2017-2022). Both conventional karyotyping and CMA were performed simultaneously on these fetuses.ResultsThe diagnostic yield of CMA in fetuses with CHD in our study was 15.3% (98/642). Our findings revealed a significant increase in the diagnostic yield of CMA compared to karyotyping in fetuses with CHD. Among CHD subgroups, the diagnostic yields were high in complex CHD (34.9%), conotruncal defects (28.6%), right ventricular outflow tract obstructive defects (RVOTO) (25.9%), atrioventricular septal defects (AVSD) (25.0%) and left ventricular outflow tract obstructive defects (LVOTO) (24.1%), while those in other CHD (10.6%) and septal defects (10.9%) were relatively low. The overall detection rate of clinically significant chromosomal abnormalities was significantly higher in the non-isolated CHD group compared to the isolated CHD group (33.1% vs. 9.9%, P < 0.0001). Interestingly, numerical chromosomal abnormalities were more likely to occur in the non-isolated CHD group than in the isolated CHD group (20.3% vs. 2.0%, P < 0.0001). The rate of termination of pregnancy (TOP)/Still birth in the non-isolated CHD group was significantly higher than that in the isolated CHD group (40.5% vs. 20.6%, P < 0.0001). Compared to the isolated CHD group, the detection rate of clinically significant chromosomal abnormalities was significantly higher in the group of CHD with soft markers (35.6% vs. 9.9%, P < 0.0001) and in the group of CHD with additional structural anomalies (36.1% vs. 9.9%, P < 0.0001).ConclusionsCMA is a reliable and high-resolution technique that should be recommended as the front-line test for prenatal diagnosis of fetuses with CHD. The prevalence of chromosomal abnormalities varies greatly among different subgroups of CHD, and special attention should be given to prenatal non-isolated cases of CHD, especially those accompanied by additional structural anomalies or soft markers.
| S-EPMC11342572 | biostudies-literature
Project description:ObjectivesPresumably, changes in fetal circulation contribute to the delay in maturation of the cortex in fetuses with congenital heart defect (CHD). The aim of the current study is to analyze fetal brain development based on hemodynamic differences, using novel brain-age prediction software.MethodsWe have performed detailed neurosonography, including acquiring 3D volumes, prospectively in cases with isolated CHD from 20 weeks onwards. An algorithm that assesses the degree of fetal brain-age automatically was used to compare CHD cases to controls. We stratified CHD cases according to flow and oxygenation profiles by lesion physiology and performed subgroup analyses.ResultsA total of 616 ultrasound volumes of 162 CHD cases and 75 controls were analyzed. Significant differences in maturation of the cortex were observed in cases with normal blood flow toward the brain (-3.8 days, 95%CI [-5.5; -2.0], P = <.001) and low (-4.0 days, 95% CI [-6.7; -1.2] P = <.05; hypoplastic left heart syndrome[HLHS]) and mixed (-4.4 days, 95%CI [-6.4; -2.5] p = <.001) oxygen saturation in the ascending aorta (TGA) and in cardiac mixing (eg, Fallot) cases.ConclusionThe current study shows significant delay in brain-age in TGA and Fallot cases as compared to control cases. However, the small differences found in this study questions the clinical relevance.
| S-EPMC7891604 | biostudies-literature
Project description:Objective This study aims to assess head volume (HV) alterations at 11 to 14 weeks in fetuses with congenital heart defects (CHD). Methods A retrospective case-control study on 100 normal and 26 CHD fetuses was conducted. The fetuses had a first trimester scan with volume data sets stored from which HV was calculated. The mean HV and HV as a function of crown-rump length (CRL) in normal fetuses were compared with established normograms. Mean HV, HV as a function of CRL, and HV/CRL were compared between normal and CHD fetuses. Nonparametric Kruskal-Wallis H test was used with p < 0.05 considered significant. Results Overall, 83 normal and 19 CHD fetuses were included. The mean HV and HV as a function of CRL in the normal fetuses were comparable to what has been established (p = 0.451 and 0.801, respectively). The mean HV was statistically smaller in fetuses with CHD, particularly those with hypoplastic left heart (HLH): 10.7 mL in HLH versus 13.0 mL in normal fetuses (p = 0.043). The HV/CRL was statistically smaller in fetuses with CHD (p = 0.01). Conclusion Despite the small sample size, our case series suggests that alterations in HV may potentially be apparent as early as 11 to 14 weeks in CHD fetuses, particularly those with HLH. Larger prospective studies are needed to validate our findings.
| S-EPMC4907783 | biostudies-other
Project description:ObjectivesCongenital heart disease (CHD) has been associated with reduced fetal head circumference (HC), although the underlying pathophysiology remains undetermined. We aimed to define trends in fetal growth and cerebroplacental Doppler flow, and to investigate their relationship, in fetuses with CHD.MethodsThis was a retrospective study in two fetal medicine units in The Netherlands. We included all fetuses with CHD in whom Doppler flow patterns (middle cerebral artery (MCA) pulsatility index (PI), umbilical artery (UA) PI and cerebroplacental ratio (CPR)) and biometry (HC and abdominal circumference (AC)) had been measured serially after 19 weeks' gestation between January 2010 and November 2016. Fetuses were categorized into three groups based on the expected cerebral arterial oxygen saturation of their particular type of CHD: normal; mild to moderately reduced; severely reduced. Trends over time in Z-scores were analyzed using a linear mixed-effects model.ResultsA total of 181 fetuses fulfilled the inclusion criteria. Expected cerebral arterial oxygen saturation in CHD was classified as normal in 44 cases, mild to moderately reduced in 84 and severely reduced in 53. In the cohort overall, average trends over time were significant for both HC and AC Z-scores. HC Z-scores showed a tendency to decrease until 23 weeks, then to increase until 33 weeks, followed by another decrease in the late third trimester. AC Z-scores increased progressively with advancing gestation. MCA-PI and UA-PI Z-scores showed significant trends throughout pregnancy, but CPR Z-scores did not. There were no associations between expected cerebral arterial oxygen saturation and fetal growth. Average trends in MCA-PI Z-scores were significantly different between the three subgroups, whereas those in UA-PI Z-scores and in CPR Z-scores were similar between the subgroups. There was no significant association between MCA-PI and HC Z-scores.ConclusionsFetal biometry and Doppler flow patterns are within normal range in fetuses with CHD, but show trends over time. Head growth in fetuses with CHD is not associated with cerebral blood flow pattern or placental function and HC is not influenced by the cerebral arterial oxygen saturation. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
| S-EPMC6593432 | biostudies-literature
Project description:BackgroundCongenital heart disease (CHD) is common and is associated with impaired early brain development and neurodevelopmental outcomes, yet the exact mechanisms underlying these associations are unclear.PurposeTo utilize MRI data from a cohort of fetuses with CHD as well as typically developing fetuses to test the hypothesis that expected cerebral substrate delivery is associated with total and regional fetal brain volumes.Study typeRetrospective case-control study.PopulationThree hundred eighty fetuses (188 male), comprising 45 healthy controls and 335 with isolated CHD, scanned between 29 and 37 weeks gestation. Fetuses with CHD were assigned into one of four groups based on expected cerebral substrate delivery.Field strength/sequenceT2-weighted single-shot fast-spin-echo sequences and a balanced steady-state free precession gradient echo sequence were obtained on a 1.5 T scanner.AssessmentImages were motion-corrected and reconstructed using an automated slice-to-volume registration reconstruction technique, before undergoing segmentation using an automated pipeline and convolutional neural network that had undergone semi-supervised training. Differences in total, regional brain (cortical gray matter, white matter, deep gray matter, cerebellum, and brainstem) and brain:body volumes were compared between groups.Statistical testsANOVA was used to test for differences in brain volumes between groups, after accounting for sex and gestational age at scan. PFDR-values <0.05 were considered statistically significant.ResultsTotal and regional brain volumes were smaller in fetuses where cerebral substrate delivery is reduced. No significant differences were observed in total or regional brain volumes between control fetuses and fetuses with CHD but normal cerebral substrate delivery (all PFDR > 0.12). Severely reduced cerebral substrate delivery is associated with lower brain:body volume ratios.Data conclusionTotal and regional brain volumes are smaller in fetuses with CHD where there is a reduction in cerebral substrate delivery, but not in those where cerebral substrate delivery is expected to be normal.Evidence level3 TECHNICAL EFFICACY: Stage 3.
| S-EPMC7616254 | biostudies-literature