Ebstein Anomaly and Right Aortic Arch in Patient with Charge Syndrome

Ebstein anomaly is a rare congenital heart disease characterized by a varying degree of anatomical and functional abnormalities of tricuspid valve and right ventricle. It often coexists with other congenital cardiac malformations. Up to 79–89% of patients with Ebstein anomaly have interatrial communication in the form of patent oval foramen or atrial septal defect and more than one-third has other types of cardiac malformations. Association between Ebstein anomaly and right aortic arch is extremely rare and only few cases have been described in the literature so far. Much rarer than with other cardiac malformations, Ebstein anomaly is associated with non-cardiac malformations or genetic syndromes. Several cases of association between Ebstein anomaly and Charge syndrome have been reported, nevertheless, Ebstein anomaly accounts for less than 1% of cardiac defects seen in patients with Charge syndrome. In this case report, we present a unique case of a patient with Charge syndrome where both Ebstein anomaly and right aortic arch are present. The diagnosis of Ebstein anomaly and right aortic arch was established prenatally. In the first years of life, the patient did not exhibit any remarkable symptoms. However, over time, deterioration of right ventricle function and increased tricuspid regurgitation were observed, requiring consideration of surgical treatment at the age of five. In addition, delay in physical, motor, and mental development was observed and thus, at the age of five, the patient was consulted by a medical geneticist and a gene panel to test for structural heart defects was ordered. The test showed a mutation in chromodomain helicase DNA binding protein 7 (CHD7) gene, which, along with clinical features, allowed to establish a diagnosis of Charge syndrome. To the best of the authors’ knowledge, this is the first case report of a patient with Charge syndrome, Ebstein anomaly, and right aortic arch that has been described in the literature.

A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes

Congenital heart disease (CHD) is the most common type of birth defect, affecting ~1% of all live births. Malformations of the cardiac outflow tract (OFT) account for ~30% of all CHD and include a range of CHDs from bicuspid aortic valve (BAV) to tetralogy of Fallot (TOF). We hypothesized that transcriptomic profiling of a mouse model of CHD would highlight disease-contributing genes implicated in congenital cardiac malformations in humans. To test this hypothesis, we utilized global transcriptional profiling differences from a mouse model of OFT malformations to prioritize damaging, de novo variants identified from exome sequencing datasets from published cohorts of CHD patients. Notch1+/−; Nos3−/− mice display a spectrum of cardiac OFT malformations ranging from BAV, semilunar valve (SLV) stenosis to TOF. Global transcriptional profiling of the E13.5 Notch1+/−; Nos3−/− mutant mouse OFTs and wildtype controls was performed by RNA sequencing (RNA-Seq). Analysis of the RNA-Seq dataset demonstrated genes belonging to the Hif1α, Tgf-β, Hippo, and Wnt signaling pathways were differentially expressed in the mutant OFT. Mouse to human comparative analysis was then performed to determine if patients with TOF and SLV stenosis display an increased burden of damaging, genetic variants in gene homologs that were dysregulated in Notch1+/−; Nos3−/− OFT. We found an enrichment of de novo variants in the TOF population among the 1,352 significantly differentially expressed genes in Notch1+/−; Nos3−/− mouse OFT but not the SLV population. This association was not significant when comparing only highly expressed genes in the murine OFT to de novo variants in the TOF population. These results suggest that transcriptomic datasets generated from the appropriate temporal, anatomic and cellular tissues from murine models of CHD may provide a novel approach for the prioritization of disease-contributing genes in patients with CHD.

Antithyroid drug treatment and pregnancy outcomes among women with hyperthyroidism in pregnancy: A Norwegian population-based registry-linkage study

Aims: The aim of this study was two-fold: i) to describe factors associated with antithyroid drug (ATD) treatmentduring gestation among women with hyperthyroidism in pregnancy, ii) to investigate the impact of ATDtreatment during gestation on pregnancy outcomes.Methods: Women with hyperthyroidism in pregnancy and ATD treatments were identified through linkage ofthree national registries (2008-2018): The Medical Birth Registry of Norway, the Norwegian PrescriptionRegistry and the Norwegian Patient Registry. Pregnancies were categorized as ATD treated or untreated basedon filled prescriptions indicating ATD exposure during pregnancy. ATD treatment was examined by trimester(T1, T2/T3) and by substance carbimazole (CMZ), propylthiouracil (PTU) and by both CMZ/PTU. Generalizedestimating equations analysis with a robust variance estimator was used to estimate adjusted odds ratio (aOR)and adjusted standardized mean difference (aSMD) with 95% confidence interval (CI).Results: We identified 1699 pregnancies with hyperthyroidism during gestation. Hyperthyroidism was treatedwith ATD in 44.4% of the pregnancies, while 55.6% were untreated. Pregnant women treated with ATD hadmore often asthma compared to untreated women. Prenatal exposure to CMZ was associated with increased riskof preterm birth (aOR 1.8, 95% CI 1.1-2.8) whereas PTU exposure in the first trimester was associated with anincreased risk of cardiac malformations (aOR 9.0, 95% CI 1.8-44.7). There was no association between ATDtreatment in pregnancy and maternal preeclampsia (aOR 0.8, 95% CI 0.4-1.3) and gestational hypertension (aOR0.9, 95% CI 0.5-1.8).Conclusion: This nationwide registry study found an association between treatment with carbimazole and increasedrisk of preterm birth. Exposure to propylthiouracil in the first trimester was associated with an increasedrisk of cardiac malformations. These findings should be interpreted in light of international findings on the riskof untreated hyperthyroidism and the potential risk of ATD treatment for the mother and child.

Prenatal diagnosis of a right ventricular outpouching: a report of case

We report a case of a right ventricular outpouching diagnosed during prenatal period. We defined it as an aneurysm because of its thin, hypokinetic wall, and wide neck connecting to the ventricle. Ventricular aneurysms, especially right ventricular aneurysms, are very rare cardiac malformations. Therefore, we describe a rare case of right ventricular aneurysm and the diagnostic features, differential diagnosis, and clinical features of ventricular aneurysms.

Glypican-6 deficiency causes dose-dependent conotruncal congenital heart malformations through abnormal remodelling of the endocardial cushions

Tetralogy of Fallot (TOF) is considered to be the commonest type of cyanotic congenital heart disease (CHD). A previous GWAS showed significant association between TOF and single nucleotide polymorphisms in chromosome 13q31. Here through integration of population genomic and chromosomal interaction data we identify the heparan sulfate proteoglycan glypican-6 (GPC6) as the potentially responsible gene at the associated locus. We showed that GPC6 is expressed in the endocardial cushions at the appropriate time in development to contribute to TOF risk. We generated mice homozygous for a Gpc6 KO allele, which exhibit 100% neonatal lethality with severe cardiac malformations, namely TOF-type double outlet right ventricle (DORV) with rightward mal-positioned aorta and perimembranous ventricular septal defect (VSD), together with right ventricular (RV) hypertrophy and narrowing of the pulmonary artery. We established a dose-response relationship between Gpc6 expression and the anatomical severity of cardiac malformations. We showed the mouse knockout phenotype arises from abnormal morphology of the endocardial cushions, and tissue-specific knockout of Gpc6 in endothelial and neural crest cell lineages produces a phenotype featuring VSD and aortic malposition analogous to human TOF. This successful identification of a CHD gene from GWAS data suggests that larger GWA studies may find additional causative genes.