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Deletions that include the gene TAB2 and TAB2 loss-of-function variants have previously been associated with congenital heart defects and cardiomyopathy. However, other features, including short stature, facial dysmorphisms, connective tissue abnormalities and a variable degree of developmental delay, have only been mentioned occasionally in literature and thus far not linked to TAB2. In a large-scale, social media-based chromosome 6 study, we observed a shared phenotype in patients with a 6q25.1 deletion that includes TAB2. To confirm if this phenotype is caused by haploinsufficiency of TAB2 and to delineate a TAB2-related phenotype, we subsequently sequenced TAB2 in patients with matching phenotypes and recruited patients with pathogenic TAB2 variants detected by exome sequencing. This identified 11 patients with a deletion containing TAB2 (size 1.68-14.31 Mb) and 14 patients from six families with novel truncating TAB2 variants. Twenty (80%) patients had cardiac disease, often mitral valve defects and/or cardiomyopathy, 18 (72%) had short stature and 18 (72%) had hypermobility. Twenty patients (80%) had facial features suggestive for Noonan syndrome. No substantial phenotypic differences were noted between patients with deletions and those with intragenic variants. We then compared our patients to 45 patients from the literature. All literature patients had cardiac diseases, but syndromic features were reported infrequently. Our study shows that the phenotype in 6q25.1 deletions is caused by haploinsufficiency of TAB2 and that TAB2 is associated not just with cardiac disease, but also with a distinct phenotype, with features overlapping with Noonan syndrome. We propose the name "TAB2-related syndrome".

ObjectiveObesity and cardiovascular disease are major global public health problems. Maternal obesity has been linked to multiple adverse health consequences for both mother and baby. Obesity during pregnancy may adversely alter the intrauterine environment, which has been hypothesised to predispose the offspring to poorer cardiovascular health throughout life. In this paper, we systematically review current literature examining the links between maternal obesity and offspring cardiovascular health.MethodsThis study is registered with PROSPERO (CRD42021278567) and was conducted in accordance with the PRISMA guidelines. A comprehensive systematic literature search was conducted, including two electronic databases (Ovid Medline, Embase), cross-referencing, author searching, and grey literature searches. We selected studies exploring the relationship between maternal obesity and offspring cardiovascular health, using pre-defined eligibility criteria. Studies were critically appraised using the ROBINS-I tool.ResultsFrom 1,214 results, 27 articles met the eligibility criteria. Multiple cardiovascular outcomes were considered, including congenital heart disease, cardiometabolic parameters, and cardiovascular diseases in neonates, children, and adults. In these studies, maternal obesity was consistently associated with congenital heart disease, several adverse cardiometabolic parameters throughout life including higher body mass index and insulin levels, and greater risk of cardiovascular disease in adulthood. Hypothesized underlying mechanisms are complex and multifactorial comprising genetic, environmental, and socioeconomic components, which can be difficult to quantify. Heterogeneity in study designs, highly selected study samples, and high risk of bias in some studies limit conclusions regarding causality.ConclusionsWe identified consistent evidence of links between maternal obesity and poorer offspring cardiovascular health throughout the lifecourse, extending from the neonatal period into adulthood. Although underlying mechanisms are unclear, our findings support consideration of targeted maternal obesity prevention for promotion of offspring cardiovascular health. This all-encompassing systematic review provides critical appraisal of the latest evidence, defines gaps and biases of existing literature, and may inform potential new public health strategies for cardiovascular disease prevention.Systematic Review Registration[https://www.crd.york.ac.uk/prospero], identifier PROSPERO (CRD42021278567).

Copy number variants of SLC2A3, which encodes the glucose transporter GLUT3, are associated with several neuropsychiatric and cardiac diseases. Here, we report the successful reprogramming of peripheral blood mononuclear cells from two SLC2A3 duplication and two SLC2A3 deletion carriers and subsequent generation of two transgene-free iPSC clones per donor by Sendai viral transduction. All eight clones represent bona fide hiPSCs with high expression of pluripotency genes, ability to differentiate into cells of all three germ layers and normal karyotype. The generated cell lines will be helpful to enlighten the role of glucometabolic alterations in pathophysiological processes shared across organ boundaries.

Copy number variants of SLC2A3, which encodes the glucose transporter GLUT3, are associated with several neuropsychiatric and cardiac diseases. Here, we report the successful reprogramming of peripheral blood mononuclear cells from two SLC2A3 duplication and two SLC2A3 deletion carriers and subsequent generation of two transgene-free iPSC clones per donor by Sendai viral transduction. All eight clones represent bona fide hiPSCs with high expression of pluripotency genes, ability to differentiate into cells of all three germ layers and normal karyotype. The generated cell lines will be helpful to enlighten the role of glucometabolic alterations in pathophysiological processes shared across organ boundaries.

Background: Recent studies reported an association between prenatal propylthiouracil exposure and birth defects, including abnormal arrangement across the left-right body axis, suggesting an association with heterotaxy syndrome. Methods: This case-control and case-finding study used data from 1981 to 2013 from the EUROCAT birth defect registry in the Northern Netherlands. First, we explored prenatal exposures in heterotaxy syndrome (cases) and Down syndrome (controls). Second, we describe the specific birth defects in offspring of mothers using propylthiouracil (PTU) prenatally. RESULTS: A total of 66 cases with heterotaxy syndrome (incidence 12.1 per 100,000 pregnancies) and 783 controls with Down syndrome (143.3 per 100,000 pregnancies) were studied. No differences in intoxication use during pregnancy were found between cases and controls, including smoking (28.0% vs. 22.7%; p = 0.40), alcohol (14.0% vs. 26.9%; p = 0.052), and recreational drugs (0 vs. 0.3%; p = 1.00). We found an association between heterotaxy syndrome and prenatal drug exposure to follitropin-alfa (5.6% vs. 1.1%; p = 0.04), and drugs used in nicotine dependence (3.7% vs. 0.2%; p = 0.02). Five mothers used PTU during pregnancy and gave birth to a child with trisomy 18, renal abnormalities, or hypospadias and cardiac defects. Conclusion: This study identified follitropin-alfa and drugs used in nicotine dependence as possible teratogens of heterotaxy syndrome. Our data suggest the possibility that there is an increased risk of birth defects (including renal, urological, and cardiac abnormalities) in children born among mothers taking PTU prenatally, but not for heterotaxy syndrome. (C) 2016 Wiley Periodicals, Inc.

Background: Recent studies reported an association between prenatal propylthiouracil exposure and birth defects, including abnormal arrangement across the left-right body axis, suggesting an association with heterotaxy syndrome. Methods: This case-control and case-finding study used data from 1981 to 2013 from the EUROCAT birth defect registry in the Northern Netherlands. First, we explored prenatal exposures in heterotaxy syndrome (cases) and Down syndrome (controls). Second, we describe the specific birth defects in offspring of mothers using propylthiouracil (PTU) prenatally. RESULTS: A total of 66 cases with heterotaxy syndrome (incidence 12.1 per 100,000 pregnancies) and 783 controls with Down syndrome (143.3 per 100,000 pregnancies) were studied. No differences in intoxication use during pregnancy were found between cases and controls, including smoking (28.0% vs. 22.7%; p = 0.40), alcohol (14.0% vs. 26.9%; p = 0.052), and recreational drugs (0 vs. 0.3%; p = 1.00). We found an association between heterotaxy syndrome and prenatal drug exposure to follitropin-alfa (5.6% vs. 1.1%; p = 0.04), and drugs used in nicotine dependence (3.7% vs. 0.2%; p = 0.02). Five mothers used PTU during pregnancy and gave birth to a child with trisomy 18, renal abnormalities, or hypospadias and cardiac defects. Conclusion: This study identified follitropin-alfa and drugs used in nicotine dependence as possible teratogens of heterotaxy syndrome. Our data suggest the possibility that there is an increased risk of birth defects (including renal, urological, and cardiac abnormalities) in children born among mothers taking PTU prenatally, but not for heterotaxy syndrome. (C) 2016 Wiley Periodicals, Inc.

Atrioventricular septal defects often result from impaired endocardial cushion development. Endothelial-to-mesenchymal transition (EndoMT) is a critical event in endocardial cushion development that initiates in the atrioventricular canal (AVC). In ex vivo EndoMT studies, mouse AVCs are flat-mounted on a collagen gel. In the explant outgrowths, the ratio of elongated spindle-like mesenchymal cells over cobblestone-shaped cells, generally considered as endothelial cells, reflects EndoMT. Using this method, several key signalling pathways have been attributed important functions during EndoMT. Using genetic lineage tracing and cell-type-specific markers, we show that monolayers of cobblestone-shaped cells are predominantly of epicardial rather than endothelial origin. Furthermore, this epicardium is competent to undergo mesenchymal transition. Contamination by epicardium is common and inherent as this tissue progressively attaches to AVC myocardium. Inhibition of TGFβ signalling, previously shown to blunt EndoMT, caused an enrichment in epicardial monolayers. The presence of epicardium thus confounds interpretations of EndoMT signalling pathways in this assay. We advocate to systematically use lineage tracers and cell-type-specific markers on stage-matched AVC explants. Furthermore, a careful reconsideration of earlier studies on EndoMT using this explant assay may identify unanticipated epicardial effects and/or the presence of epicardial-to-mesenchymal transition (EpiMT), which would alter the interpretation of results on endothelial-to-mesenchymal transition. ispartof: SCIENTIFIC REPORTS vol:8 issue:1 ispartof: location:England status: published

Congenital heart defects (CHDs), the most commonly occurring congenital malformations, cause significant mortality and morbidity. With the recognition of early markers for CHD and the development of better ultrasound resolution, interest has turned toward performing a screening anomaly scan, including the heart, together with the nuchal scan. It is also possible, with adequate skill and training, to competently perform an echocardiogram

Congenital heart defects (CHDs), the most commonly occurring congenital malformations, cause significant mortality and morbidity. With the recognition of early markers for CHD and the development of better ultrasound resolution, interest has turned toward performing a screening anomaly scan, including the heart, together with the nuchal scan. It is also possible, with adequate skill and training, to competently perform an echocardiogram

Aim Pulse oximetry screening of newborn infants increases early detection of critical congenital heart disease and minimises the risk of circulatory collapse before surgery. This study provides an update on the implementation of pulse oximetry screening in the Nordic countries and proposes standardised guidelines. Methods A questionnaire exploring pulse oximetry screening, clinical examination routines and availability of echocardiography was distributed to all 157 delivery units in the Nordic countries in June 2013. Results We received responses from 156 of the 157 delivery units, and 116 (74%) were using pulse oximetry screening by September 2013. Preductal and postductal screening were both used in 59 of 116 units (51%), with just postductal screening in 51 of 116 (44%) and just preductal screening alone in 6 of 116 (5%). Screening was performed before 24 h in 105 of 116 units (91%). The implementation of screening was highest in Finland (29/30, 97%), Sweden (42/46, 91%) and Norway (43/48, 90%) and lowest in Denmark (2/24, 8%) and Iceland (0/8 units). Conclusion In Sweden, Norway and Finland, the implementation of pulse oximetry screening is currently the highest in the world and coverage will be close to 100% in 2014. We propose uniform Nordic guidelines using preductal and postductal screening before 24 h of age.

Over the years, it has become clear that increased nuchal translucency is a marker for chromosomal abnormalities, and it is also associated with a wide spectrum of structural anomalies, genetic syndromes, a higher risk of miscarriage, and intrauterine fetal death. These risks are all proportionally related to the degree of nuchal translucency enlargement.After the initial assessment of increased nuchal translucency, parents should be counselled by the fetal medicine specialist about the possible outcomes and the value of additional karyotyping and array comparative genomic hybridisation. A detailed late first-trimester and subsequent 20-week scan should aim at identifying structural anomalies, with special focus on the fetal heart and subtle dysmorphic features. In the absence of structural anomalies or markers, the chance of a favourable outcome is high. (C) 2013 Elsevier Ltd. All rights reserved.

Background The effects of many drugs on the unborn child are unknown. In a case-population design, drug exposure of cases is compared with that of a source population; this kind of study can be useful for generating signals.Objective To see whether a comparison of drug use rates from the birth defect registry EUROCAT NNL (cases) with prescription rates from a population-based prescription database, the IADB (population), could be used to detect signals of teratogenic risk of drugs.Methods We defined 3,212 cases from the EUROCAT NNL database, a population-based birth defect registry in the Northern Netherlands and 29,223 population controls from the IADB, a prescription database with data from community pharmacies in the same geographical area, born between 1998 and 2008. We classified the malformations of the 3,212 cases into several malformation groups according to organ system (based on the International Classification of Diseases codes and the EUROCAT guidelines). If a child had multiple malformations in several organ systems (n = 253, 7.9 %), he/she was counted in all the categories represented. For several groups of malformations we calculated rate ratios (RR) and 95 % confidence intervals for drugs acting on the central nervous system and for drugs considered to be safe for use in pregnancy. The RRs were based on first-trimester drug use rates from the cases in the EUROCAT NNL database and prescription rates from the population controls in the IADB.Results For drugs acting on the central nervous system we found significantly increased RRs for the anti-epileptic drug valproic acid and for some selective serotonin reuptake inhibitors. For drugs considered to be safe only the anti-hypertensive methyldopa showed significantly increased RRs.Conclusion We show that a case-population study is a suitable method for detecting signals of possible teratogenicity, provided that the teratogenic effects and the drugs under study are as specific as possible and the drugs are widely used.

Recent studies reported an association between prenatal propylthiouracil exposure and birth defects, including abnormal arrangement across the left-right body axis, suggesting an association with heterotaxy syndrome. This case-control and case-finding study used data from 1981 to 2013 from the EUROCAT birth defect registry in the Northern Netherlands. First, we explored prenatal exposures in heterotaxy syndrome (cases) and Down syndrome (controls). Second, we describe the specific birth defects in offspring of mothers using propylthiouracil (PTU) prenatally. A total of 66 cases with heterotaxy syndrome (incidence 12.1 per 100,000 pregnancies) and 783 controls with Down syndrome (143.3 per 100,000 pregnancies) were studied. No differences in intoxication use during pregnancy were found between cases and controls, including smoking (28.0% vs. 22.7%; p = 0.40), alcohol (14.0% vs. 26.9%; p = 0.052), and recreational drugs (0 vs. 0.3%; p = 1.00). We found an association between heterotaxy syndrome and prenatal drug exposure to follitropin-alfa (5.6% vs. 1.1%; p = 0.04), and drugs used in nicotine dependence (3.7% vs. 0.2%; p = 0.02). Five mothers used PTU during pregnancy and gave birth to a child with trisomy 18, renal abnormalities, or hypospadias and cardiac defects. This study identified follitropin-alfa and drugs used in nicotine dependence as possible teratogens of heterotaxy syndrome. Our data suggest the possibility that there is an increased risk of birth defects (including renal, urological, and cardiac abnormalities) in children born among mothers taking PTU prenatally, but not for heterotaxy syndrome. Birth Defects Research (Part A) 106:573-579, 2016. © 2016 Wiley Periodicals, Inc

Endocardial cushion defects (ECDs) of the cardiac outflow tract are among the most common congenital heart disease phenotypes. VEGF is essential for endocardial cushion formation and derangements in VEGF synthesis lead to ECD. Three functional single nucleotide polymorphisms (SNPs) in the VEGF gene -2578 C>A, -1154 G>A, and -634 G>C play a role in cardiogenesis. In a Dutch case-control family study of triads, 190 case and 317 control children with both parents, we investigated linkage and association between these VEGF SNPs and ECD. Allele frequencies for the three VEGF SNPs were comparable between ECD children and controls. However, VEGF alleles -2578 C and 1154 G were transmitted more frequently to children with ECD (p = 0.003 and p = 0.002), in particular perimembranous ventricular septal defects (p = 0.012 and p = 0.006). The -2578A/-1154A/-634G haplotype was associated with a reduced risk of ECD (OR 0.7: 95% CI, 0.6-1.0) and was significantly less transmitted to children with ECD U) = 0.002). In a Dutch population, we show that the VEGF 2578 C, -1154 G alleles, and the AAG haplotype are associated with ECD. Possible VEGF gene-enviromnent interactions exposures are discussed. (Pediatr Res 67: 23-28, 2010)

Endocardial cushion defects (ECDs) of the cardiac outflow tract are among the most common congenital heart disease phenotypes. VEGF is essential for endocardial cushion formation and derangements in VEGF synthesis lead to ECD. Three functional single nucleotide polymorphisms (SNPs) in the VEGF gene -2578 C>A, -1154 G>A, and -634 G>C play a role in cardiogenesis. In a Dutch case-control family study of triads, 190 case and 317 control children with both parents, we investigated linkage and association between these VEGF SNPs and ECD. Allele frequencies for the three VEGF SNPs were comparable between ECD children and controls. However, VEGF alleles -2578 C and 1154 G were transmitted more frequently to children with ECD (p = 0.003 and p = 0.002), in particular perimembranous ventricular septal defects (p = 0.012 and p = 0.006). The -2578A/-1154A/-634G haplotype was associated with a reduced risk of ECD (OR 0.7: 95% CI, 0.6-1.0) and was significantly less transmitted to children with ECD U) = 0.002). In a Dutch population, we show that the VEGF 2578 C, -1154 G alleles, and the AAG haplotype are associated with ECD. Possible VEGF gene-enviromnent interactions exposures are discussed. (Pediatr Res 67: 23-28, 2010)

B vitamin deficiencies lead to moderate hyperhomocysteinemia, which has been associated with health and disease. However, concomitant derangements in cellular methylation, reflected by altered plasma S-adenosylmethionine (SAM) or S-adenosylhomocysteine (SAH) concentrations, may be the primary cause. Therefore, we identified determinants of homocysteine, SAM, and SAH concentrations in 336 women, aged 20-48 y, as part of a large study focusing on risk factors for reproductive disorders, Blood was obtained to determine plasma SAM, SAH, and total homocysteine (tHcy), serum vitamin B-12 and folate, RBC folate concentrations, and the related single nucleotide polymorphisms 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C > T and 1298A > C, methionine synthase reductase (MTRR) 66A > G, and nicotinamide A methyltransferase IVS1-151G > A. Questionnaires provided information on demographics, lifestyles, and nutrient intakes. Correlation coefficients were calculated and multivariable associations were assessed with a general linear model. Serum folate was positively correlated with SAM concentrations (r = 0.159; P = 0.004). Folate and vitamin B-12 were not correlated with SAH concentrations or the SAM:SAH ratio but were inversely correlated with tHcy concentrations (serum folate r = -0.324; RBC folate r = -0.294; vitamin B-12 r = -0.307; P < 0.01). From the multivariable analysis, BMI was the strongest determinant of SAM (standardized beta = 19.145; P < 0.001) and SAH concentrations (standardized beta = 3.241; P = 0.010). MTHFR 677TT (standardized beta = 0.195; P = 0.001), B vitamin supplement use (standardized beta = -0.156; P < 0.001) and dietary protein intake (standardized beta = -0.011; P < 0.001) were the strongest determinants of tHcy concentrations. Thus, the determinants of SAM and SAH differ from those of tHcy concentrations. Given that BMI was a strong determinant of SAM concentrations, it should be included in future studies on cellular methylation. J. Nutr. 139: 2315-2321, 2009.