Identification and functional analysis of biallelic loss-of-function variants of WNT7B in a Chinese family affected with PDAC syndrome.

Advanced paternal age at birth and risk of cyanotic congenital heart defects in the United States.

Multi-object Tracking-based Detection of Cardiac Septal Defects in Echocardiography Videos

Background: Triple X syndrome is the most common sex chromosome aneuploidy in females; however, due to the subtlety of clinical findings, only a small proportion of affected individuals are diagnosed. This study presents the demographic, clinical, and cytogenetic characteristics of patients with Triple X syndrome followed at a single center. Methods: We retrospectively reviewed the medical records of patients diagnosed with Triple X syndrome at our department between 2008 and 2025. Demographic characteristics, clinical findings including anthropometric measurements, dysmorphic features, associated anomalies, endocrine and neurodevelopmental findings, and cytogenetic results were analyzed. Results: The study included a total of 20 patients diagnosed with Triple X syndrome, 13 of whom (65%) had a non-mosaic 47,XXX karyotype and 7 (35%) had mosaic chromosomal abnormalities. Four patients received a prenatal diagnosis, four were diagnosed in adulthood, and the remaining patients were diagnosed during childhood. Dysmorphic features; neurodevelopmental problems such as developmental delay, intellectual disability, and attention-deficit/ hyperactivity disorder; as well as cardiac defects and endocrine disorders were the main characteristics observed in the patients. Conclusion: Triple X syndrome is a relatively common chromosomal disorder, which should be considered in patients who experience congenital anomalies, neurodevelopmental abnormalities, and reproductive problems. Variable and subtle findings should be carefully considered, bearing in mind that mosaic cases may present with diverse and overlapping phenotypes.

Contribution of AhR-mediated activation of the AC/cAMP/PKA cascade to 6PPDQ-induced cardiac defects in zebrafish.

Inhaled nitric oxide (iNO) is a commonly used pulmonary vasodilator in neonates, but its effects on intestinal perfusion remain unclear. This study assessed the impact of iNO on splanchnic tissue oxygenation as a surrogate for intestinal perfusion using near infrared spectroscopy (NIRS), with NG-nitro-L-arginine methyl ester (L-NAME) used to inhibit endogenous nitric oxide synthase (NOS) and isolate the effect of exogenous NO. Seventeen piglets (7-10 days old) were anesthetized and ventilated with NIRS probes placed on the forehead and abdomen. Piglets were allocated to group 1 (n = 4) receiving iNO only, group 2 (n = 6) receiving iNO then L-NAME, and group 3 (n = 7) receiving L-NAME then iNO. Serum nitrate/nitrite and endothelin-1 expression were assessed via colorimetric assay and ELISA. iNO increased splanchnic oxygenation, significantly reducing the difference between cerebral and abdominal NIRS. This effect was blunted by L-NAME pre-treatment (p = 0.02 at 0 and 60 ppm). Serum nitrate/nitrite and endothelin-1 levels did not differ significantly between groups, nor did mean arterial pressure. iNO enhances splanchnic tissue oxygenation to near cerebral levels. Pretreatment with L-NAME eliminates this effect, suggesting a role for endogenous NOS in this process. These findings suggest a potential protective role of iNO against intestinal ischemia and merit further investigation. As shown in previous studies, there are extrapulmonary effects of inhaled nitric oxide (iNO) on tissue perfusion; this study specifically validates this by evaluating oxygenation of the gut. iNO increases splanchnic tissue oxygenation to cerebral levels. This preclinical research establishes improvement in intestinal oxygenation with iNO use in contrast to other studies proposing iNO as a potential contributor to the development of NEC in the setting of cardiac defects. This study suggests that iNO could be a potential therapeutic agent in ischemic intestinal conditions.

Objectives: Down Syndrome (DS) is a common aneuploidy involving chromosome 21, wherein abnormalities in folate pathway are documented in several studies. Dysregulation of methylene tetra hydro folate reductase (MTHFR) activity leads to altered homocysteine levels, which is a risk factor for vascular diseases. The two functionally relevant polymorphisms C677T and A1298C in MTHFR gene are associated with various thromboembolic events. The comorbidities in DS include congenital cardiac defects (CCD), thyroid disorders and subnormal intellect. However, the correlation between these comorbidities in DS with several parameters viz. homocysteine or cysteine levels as well as MTHFR polymorphisms are not fully explored. Therefore, the present study is an attempt to investigate these parameters in DS children. Material and Methods: Seventy-five individuals with DS and thirty age and sex matched healthy control children were enrolled with informed consent for this study. The homocysteine and cysteine levels were quantitated using LC-MS while Sanger method was used for sequencing of MTHFR polymorphisms. Results: Significantly higher levels of cysteine were observed in DS children. Analysis of the two MTHFR variants revealed over representation of 677T and 1298C in children with DS compared to the healthy controls. On stratified analysis it was observed that DS children with comorbidities (hypothyroidism and/or congenital heart defect) had overrepresentation of MTHFR 677T and 1298C along with significantly higher levels of homocysteine and cysteine as compared to patients without comorbidities. Conclusion: Our findings suggest that MTHFR variants (677T, 1298C) along with elevated homocysteine and cysteine levels may serve as potential biomarkers for hypothyroidism in Down syndrome. Our results could be predictive for DS associated comorbidities with scope for better prognostication and counselling in these patients.

Neonates comprise a special population of patients undergoing surgery, and the presence of congenital defects further complicates their anaesthetic management. This report describes a neonate born with Arnold-Chiari malformation and a ruptured myelomeningocele, who was later found to also have a double-outlet right ventricle. This report outlines the careful selection of anaesthetic agents and perioperative strategies tailored to the patient's compounded neurologic and cardiac congenital defects while catering to the surgical requirements. The patient underwent repair of the MMC under total intravenous anaesthesia induced with midazolam, ketamine and atracurium and maintained with a combination of dexmedetomidine and fentanyl. The combination of dexmedetomidine and fentanyl appears to be a viable option for neonates with rigid perioperative haemodynamic goals and a need for neuroprotection. We report the safe use of dexmedetomidine for total intravenous anaesthesia pending more robust evidence in this patient population.

Down syndrome is associated with multisystem comorbidities complicating perioperative care, including cervical spine instability, airway abnormalities, and cardiac conduction defects. We report the case of a child with Down syndrome, high cervical myelopathy, progressing quadriplegia, and an abdominal cardiac pacemaker undergoing laparoscopic diaphragm pacer implantation. Management required advanced airway planning and coordinated pacemaker reprogramming to prevent device interference and arrhythmia. Continuous electrophysiologic monitoring was maintained throughout the procedure. The patient tolerated implantation without complication and achieved improved respiratory function with decreased ventilatory dependence. This case emphasizes the importance of multidisciplinary collaboration when multiple pacing systems coexist.

Minimally invasive occluder implantation effectively treats congenital heart disease by sealing cardiac defects. However, it still faces issues of inadequate endothelialization and tissue healing capabilities in clinical practice. In this study, we propose an extracellular matrix (ECM)-biomimetic microenvironment-regulating coating, where a polyethylene glycol linker (alkyne-PEG-silane) with antifouling effects is used to graft tailored recombinant humanized collagen type I (rhCol I) possessing high cell-adhesive activity via an efficient click reaction. In vitro blood and cell experiments reveal that this coating improves hemocompatibility, promotes endothelial cell growth, and enhances cardiomyocyte function. Subcutaneous and intravascular implantations confirm the coating's ability to alleviate inflammation by polarizing inflammatory cells into an anti-inflammatory phenotype, accelerate endothelialization, and facilitate tissue repair. This work highlights the potential effectiveness of the coating in optimizing the performance of cardiac occluders, which could be a promising strategy for improving the clinical efficacy of occluders.

Rubella is a highly contagious, mild, viral infection. It is usually self-limiting, but in pregnancy, specifically in the first trimester, rubella poses significant risks. Rubella in pregnancy can have severe consequences for the fetus, including miscarriage, stillbirth and a range of congenital anomalies known collectively as congenital rubella syndrome. These anomalies are associated with lifelong complications, such as hearing impairment, cardiac defects, cataracts and neurodevelopmental delays. This article explores the background and epidemiology of rubella, recent global trends in reported rubella cases and rubella prevention and immunisation policies. It will also explore the role of the midwife in the context of rubella. In pregnancy, midwives are often the first point of contact for women, and are responsible for immunity screening, educating around the risks of rubella and facilitating vaccinations in the postnatal period.

NOX4/Keap1/Nrf2/ROS signaling drives ferroptosis in trimethyltin chloride-induced cardiac developmental malformations.

Abstract Pregnancy is a period of heightened vulnerability to toxic exposures, with each trimester representing distinct developmental stages. In Nigeria and across sub-Saharan Africa, pregnant women are commonly exposed to various pharmaceuticals such as antidepressants, antibiotics, contraceptives, antiemetics, vitamins, and antidiabetics, as well as chemicals including alcohol, pesticides, and industrial pollutants like lead and mercury. This narrative review summarizes trimester-specific outcomes and mechanisms of toxicity based on published studies from Nigeria and Africa. Evidence shows that many pregnant women self-medicate or inadvertently consume hazardous substances. About 22.6% of Nigerian women report alcohol use during pregnancy, and nearly 30% self-medicate with drugs such as paracetamol, antimalarials, and antibiotics. First-trimester exposures, when organogenesis occurs, are most strongly linked to structural anomalies like neural tube and cardiac defects, whereas later exposures impair fetal growth and neurodevelopment. Prenatal selective serotonin reuptake inhibitors (particularly paroxetine and fluoxetine) are associated with cardiac and cranial malformations, while antibiotics such as tetracyclines and fluoroquinolones may cause skeletal or cartilage toxicity. Alcohol is a potent teratogen causing fetal alcohol spectrum disorders at any stage. Pesticide exposure in early pregnancy is linked to neural and limb malformations, and lead exposure contributes to miscarriage, preterm birth, low birth weight, and neurodevelopmental deficits. Regional statistics and study data are summarized in tables, with case reports highlighting Nigerian infants affected by fetal alcohol syndrome and lead poisoning. The findings emphasize an urgent need for improved education, regulation, and prenatal screening to reduce these risks in Africa.

The neurodevelopmental outcome of 'Cystic' malformations of the posterior fossa with marked opening of the fourth ventricle, such as Dandy Walker malformation (DWM) and large Blake's pouch cyst (BPC), is a major issue. This study aimed to refine relevant MRI criteria for distinguishing DWM from BPC and identify prognostic factors. Inclusion criteria were prenatal retrocerebellar fluid space diameter >10mm, marked opening of the fourth ventricle with a tegmento-vermian angle (TVA)>40°, and postnatal follow-up > 2years. 27 patients were classified as follows: 6 DWM characterized by an overall upward orientation of the tentorium, an open tegmento-tentorial angle (TTA>78) and a high TVA (median 132°); 15 BPC with a normal downward orientation of the proximal part of the tentorium (TTA<68°) and distal upward displacement (median TVA 74°); 3 PHACE syndromes (Posteriorfossa abnormalities, Haemangioma, Arterial cerebrovascular anomalies, Cardiac defects, Eye anomalies) and 3 unclassified. Four prognostic factors were identified, (i) diagnosis: DWM (two deaths, three learning disabilities and one typical development (TD)) versus BPC (five learning disabilities [4/5 with associated malformation or genetic defects] and 10 TD); (ii) associated versus isolated (36% vs. 87% TD); (iii) obstructive ventriculomegaly versus no hydraulic complications (20% vs. 91% TD); and (iv) the foetal TVA value and clinical outcome (correlation coefficient=0.561, p=0.006).

To characterize the prenatal sonographic features across different trimesters and genomic spectrum of NONO-related X-linked intellectual developmental disorder. We analyzed two fetuses presenting with corpus callosum agenesis and rare cardiac anomalies using genome sequencing and exome sequencing. A systematic literature review was conducted to provide a comprehensive analysis of genotype-phenotype correlations. Two novel cases were reported in this study: one with a de novo 61.7 kb deletion affecting both NONO and ITGB1BP2, andanother with a de novo c.1093 C > T(p.Arg365Ter), a recurrent variant reported in the literature. A total of 23 cases with NONO defects and prenatal phenotypes were identified, encompassing 19 distinct variant types. Large deletions and splicing variants accounted for approximately 32% (6/19). Among all cases, 78% (18/23) exhibited typical or concurrent brain abnormalities, such as corpus callosum agenesis, cardiac defects including left ventricular noncompaction (LVNC), or short long bones in the second trimester. Notably, 4% (1/23) of cases were reported with isolated intrauterine growth restriction (IUGR), primarily identified in the third trimester. Genome sequencing facilitates thorough identification of the genetic causes of NONO-related syndrome. The recurrent variant p.Arg365Ter has been reported to cause variable cardiac abnormalities in different patients, suggesting that other genetic or non-genetic factors may contribute to the cardiac manifestations in NONO-related syndromes.

Congenital heart disease (CHD) is the most common birth defect, and its pathogenesis is closely related to the abnormal establishment of the left-right (LR) body axis, which highly depends on the ciliary function of the left-right organizer (LRO). This review systematically expounds the molecular pathways by which ciliary structural and functional abnormalities cause cardiac malformations by integrating multi-species model evidence. We believe that defects in multiple conserved genes (including CFAP45, ZIC3, FOXJ1, NEK3, APLNR, and microRNAs) disrupt ciliary assembly, motility, or signaling capacity, leading to the disappearance of the leftward nodal flow or mechanical sensing failure within the LRO. This further interrupts the left-specific calcium ion flicker and the activation of the Nodal-Pitx2 signaling cascade, ultimately resulting in failed cardiac looping and structural defects (such as ventricular septal defect and transposition of the great arteries). This review integrates transcriptional regulation, protein stability, miRNA-mediated fine regulation, and the planar cell polarity (PCP) pathway into a unified "cilia-LRO-heart" network and explores the molecular mechanisms of cilia in valve diseases and cardiac fibrosis. This not only deepens the understanding of the fundamental biological processes of heart development but also provides new molecular targets and theoretical frameworks for the genetic diagnosis and counseling of related congenital heart diseases.

Activating transcription factor 4 (ATF4) functions as a transcriptional regulator in various cell types and tissues under both physiological and pathological conditions. While previous studies have linked ATF4 activation with promoting cardiomyocyte (CM) death in dilated cardiomyopathy (DCM), atrial fibrillation, and heart failure, its role in developing CMs remains unexplored. We generated multiple distinct CM-specific (Atf4cKO(e2/3/pA) and Atf4cKO(e2)) and global Atf4 knockout (KO; Atf47del/7del and Atf41ins/1ins) mouse models targeting different Atf4 regions, as well as CM-specific deletion of Rps19bp1 to study cardiac phenotypes. Detailed morphological and molecular analyses were performed. Atf4cKO(e2/3/pA) [targeting exon 2-3 including the polyadenylation signal (polyA)] mice exhibited severe cardiac defects and died before E17.5, likely due to ectopic activation of the p53 signaling pathway resulting from Rps19bp1 downregulation, a potent suppressor of p53. Further investigation revealed that deleting the polyA signal of Atf4 in Atf4cKO(e2/3/pA) mice led to transcriptional readthrough, resulting in the formation of an Atf4-Cacna1i fusion transcript and Rps19bp1 downregulation. To avoid readthrough while abolishing ATF4 function, we introduced small indels into exon 3 of Atf4 in mice (Atf47del/7del and Atf41ins/1ins), which showed normal Rps19bp1 expression and cardiac morphology. Importantly, CM-specific deletion of Rps19bp1 recapitulated the cardiac defects and transcriptional change seen in Atf4cKO(e2/3/pA) mice. We found that the downregulation of Rps19bp1, not the loss of ATF4 function, underlies the cardiac phenotypes in Atf4cKO(e2/3/pA) mice. The reduced expression of Rps19bp1 in Atf4cKO(e2/3/pA) mice is likely due to the unintentional deletion of Atf4 polyA signal and subsequent transcriptional readthrough, underscoring the essential role of RPS19BP1, not ATF4, in cardiac development. Consistent Rps19bp1 downregulation has been observed in other tissue-specific Atf4 KO models utilizing the Atf4fl(e2/3/pA) allele, suggesting that previously reported Atf4 KO phenotypes may result from Atf4 transcriptional readthrough effects. These findings reveal a locus-dependent transcriptional interference mechanism and emphasize the importance of avoiding confounding cis effects in genetically engineered models.

Zika virus (ZIKV) is primarily known for its impact on the fetal central nervous system potentially leading to Congenital Zika Syndrome (CZS). Emerging evidence suggests ZIKV may also affect cardiac development. We conducted a follow-up study evaluating cardiologic findings in infants from ZIKV-exposed mothers. Infants born to mothers with PCR-confirmed ZIKV infection during pregnancy and/or who had positive ZIKV PCR results at birth received echocardiograms in the first year of life. Repeat imaging within 12 months was requested for infants with identified abnormalities. Frequencies of cardiovascular (CV) abnormalities were evaluated using Pearson χ2 test, Fisher's exact test, and descriptive statistics. Predictors of CV abnormalities were assessed using multivariate logistic regression, as well as univariate and multivariate prevalence estimates. Sensitivity analysis assessed the robustness of associations when stratified by age at echocardiography (early vs late). One hundred sixty-nine children with antenatal ZIKV-exposure had echocardiograms; 30.8% were microcephalic (MC). Thirty (17.8%) had cardiac anomalies. MC children had a higher frequency of CV abnormalities than normocephalic (NC) children (26.9% vs 13.7%, p = 0.04). Twenty-four of 30 children (80.0%) returned for repeat imaging; of that group, 25.0% continued to demonstrate defects. Rates of persistent defects between the MC vs. NC cohorts were 33.3% vs 16.7%, respectively (p = 0.64). Presence of CV defects was significantly associated with MC (OR=3.40, 95% CI 1.15-10.02; p = 0.03). Among those with echocardiography performed later, MC was still associated with higher risk of abnormalities (OR=6.0, 95% CI 1.03-34.94; p = 0.046). A higher frequency of cardiac defects was noted in ZIKV-exposed infants than the general population. Most defects resolved on follow-up. The presence of a congenital heart defect (CHD) could be considered a parameter of CZS given its association with MC.

Abstract Background Surgical correction of congenital cardiac defects in infancy is being increasingly prevalent there is an increasing population of patients reaching adulthood with corrected congenital heart disease. Pregnancy in these patients can be particularly dangerous and risk stratification is key. Complications during pregnancy can still occur, which in the context of corrected congenital cardiac disease may require unique care. Case Summary A 30-year-old patient in her third trimester of pregnancy presented to hospital with acute onset chest pain and shortness of breath. She had a background of congenital corrected pulmonary atresia via a Modified Blalock-Thomas-Taussig shunt which required conduit replacements through her adolescence and a ventricular septal defect (VSD) repaired with a dacron patch. Routine echocardiograms and electrocardiograms had been stable through her pregnancy. On this occasion, she rapidly deteriorated on presentation to the emergency department and suffered a 15-minute Ventricular Fibrillation (VF) arrest during which she underwent a peri-mortem C-Section. During her cardiac arrest she developed CPR induced consciousness which led to some distressing recall of her treatment. Overall, this was felt to be scar related VF and she left hospital after a 3-week admission with an implantable cardiac defibrillator. She and her newly born baby suffered no ill effects of this cardiac arrest. Discussion This case highlights the necessity for early recognition, rapid intervention, and multidisciplinary collaboration in managing life-threatening maternal cardiac emergencies.

Myotonic dystrophy type 1 (DM1) is caused by a (CTG)n trinucleotide repeat expansion in the 3'UTR of the DMPK gene. Once expressed, repeat RNA forms toxic hairpins that sequester the MBNL (muscle blind-like) family of splicing factors. This disrupts the tissue alternative splicing landscape, triggering multisystemic manifestations-myotonia, muscle weakness, cardiac contractile defects, arrhythmia, and neurological disturbances. Although impaired mitochondrial function has been reported in the brain, skeletal muscle, and fibroblasts of patients with DM1, they have not been reported in the heart, nor have their contribution to the DM1 cardiac pathogenesis been explored. Here, we probed the bioenergetic profile of DM1-afflicted heart tissues and explored the mechanistic basis of DM1-induced cardiac bioenergetic defects. Using an inducible, heart-specific DM1 mouse model, we performed extracellular flux analyses, measured total ATP and NAD(H) concentrations, and performed immunofluorescence staining and transmission electron microscopy to characterize DM1-induced cardiac bioenergetics and mitochondrial structural defects. We analyzed eCLIP-Seq data to identify mitochondria-related missplicing events, which we validated in human and mouse DM1 heart tissues. Finally, we used antisense oligonucleotides to replicate these events and to test the recapitulation of DM1-like bioenergetic and structural defects in vitro. DM1 induced a multistate decrease in oxygen consumption rate with a corresponding reduction in ATP and NAD(H) concentrations, indicating impaired oxidative phosphorylation in DM1-afflicted mouse hearts. We also found significant cardiac mitochondria fragmentation, which correlated with the missplicing of transcripts encoding mitochondria fission factor (Mff, encodes MFF protein) and dynamin related protein 1 (Dnm1l, encodes DRP1 protein) in DM1-afflicted human and mouse hearts. Antisense oligonucleotides-mediated redirection of Dnm1l alternative splicing reproduced DM1-like impairment in cardiac bioenergetics and mitochondrial dynamics in wild-type HL-1 cardiomyocytes. Together, these findings reveal that expanded (CUG)n RNA toxicity in DM1 disrupts cardiac bioenergetics through the missplicing of critical mitochondrial fission transcripts. These misspliced transcripts represent potential therapeutic targets for improving mitochondrial function and cardiac symptoms of DM1.