Search Results (9)

When the resources are available, critical congenital heart diseases (CCHDs) should ideally be detected in utero; however, their later detection at birth can still reduce negative outcomes and risks. This study aimed to assess the extent of cardiac screening implementation in a national sample of hospitals within Mexico’s public health services. A cross-sectional survey was conducted to identify the barriers and facilitators to neonatal screening using a sample of 76 hospitals. The descriptive statistics and associations were analyzed, with significance set at p < 0.05. Only 12% of hospitals reported the routine implementation of CCHD screening, while 20% used variable screening criteria. A potential mandatory implementation of CCHD screening was associated with increased odds of perceiving the lack of protocols and guidelines as a barrier. The most frequently reported obstacles involved a lack of the following: equipment, designated physical space, trained personnel, and adequate training. Nevertheless, the facilitators identified suggest that when combined with standardized guidelines and protocols, routine nationwide implementation may be achievable. Full article

RASopathies are a diverse group of genetic conditions caused by hyperactivation of the RAS-MAPK signaling pathway, mainly inherited in an autosomal dominant manner. They present with variable features such as short stature, congenital heart defects, facial dysmorphisms, and neurodevelopmental delays. This study retrospectively analyzed 143 cases from 2003 to 2022, aiming to improve genotype–phenotype correlation knowledge for personalized care. Patients with genetically confirmed Noonan syndrome (NS) and related disorders were included, with molecular analysis performed via Sanger or parallel sequencing. Data from 906 previously reported cases were also reviewed. Among the 143 patients, most had NS (n = 116). PTPN11 mutations were most frequent (61%), followed by SOS1 (10.3%) and RAF1 (8.6%). Cardiac anomalies were observed in 71%, with pulmonary stenosis (PS) prevalent in NS (48.3%) and hypertrophic cardiomyopathy (HCM) in NSML (40%). PTPN11 variants were linked to PS and atrial septal defects, SOS1 to multiple cardiopathies, and RAF1 to HCM. Additional features included facial dysmorphisms (74.1%), short stature (62.0%), skeletal anomalies (43.1%), cryptorchidism (59.7%), and brain abnormalities (17.2%). JMML and other malignancies were seen in eight patients. This study emphasizes the importance of genotype-guided care, improved diagnosis of mild cases, and the underrecognized prevalence of neurological anomalies. Full article

Congenital heart defects (CHDs) are the most common form of birth defects in humans. They occur in 9 out of 1000 live births and are defined as structural abnormalities of the heart. Understanding CHDs is difficult due to the heterogeneity of the disease and its multifactorial etiology. Advances in genomic sequencing have made it possible to identify the genetic factors involved in CHDs. However, genetic origins have only been found in a minority of CHD cases, suggesting the contribution of non-inherited (environmental) risk factors to the etiology of CHDs. Maternal pregestational diabetes is associated with a three- to five-fold increased risk of congenital cardiopathies, but the underlying molecular mechanisms are incompletely understood. According to current hypotheses, hyperglycemia is the main teratogenic agent in diabetic pregnancies. It is thought to induce cell damage, directly through genetic and epigenetic dysregulations and/or indirectly through production of reactive oxygen species (ROS). The purpose of this review is to summarize key findings on the molecular mechanisms altered in cardiac development during exposure to hyperglycemic conditions in utero. It also presents the various in vivo and in vitro techniques used to experimentally model pregestational diabetes. Finally, new approaches are suggested to broaden our understanding of the subject and develop new prevention strategies. Full article

The TNNI3 gene encodes for the cardiac isoform of troponin I, a pivotal component of the sarcomeric structure of the myocardium. While heterozygous TNNI3 missense mutations have long been associated with autosomal dominant hypertrophic and restrictive cardiomyopathies, the role of TNNI3 null mutations has been more debated due to the paucity and weak characterization of reported cases and the low penetrance of heterozygous genotypes. In recent years, however, an increasing amount of evidence has validated the hypothesis that biallelic TNNI3 null mutations cause a severe form of neonatal dilated cardiomyopathy. Here, we expand the case series reporting two unrelated patients afflicted with early onset dilated cardiomyopathy, due to homozygosity for the p.Arg98* TNNI3 variant, which had thus far been documented only in heterozygous patients and apparently healthy carriers, and the recurrent p.Arg69Alafs*8 variant, respectively. A review of previously reported biallelic TNNI3 loss-of-function variants and their associated cardiac phenotypes was also performed. Full article

(1) Background: The interaction between single nucleotide variants (SNVs) associated with congenital heart diseases (CHDs) and their gene methylation status has not been well researched. The aim of the present study was to determine if there is a relationship between the methy lation status (MS) of genes and the allelic variants associated with CHDs. (2) Methods: Seven SNVs of the genes AXIN1, TBX1, TBX20, and MTHFR were selected from the literature. DNA extraction, genotyping, and a methylation analysis were performed on healthy subjects and subjects with CHDs. (3) Results: Twenty-two subjects with CHDs were selected as the case group (15 with ventricular septal defects (VSDs) and 7 with atrial septal defects (ASDs)), and 44 healthy subjects comprised the control group. The MTHFR and AXIN1 genes were hypermethylated in the control group when compared to the case group. When analyzed separately, those with atrial septum defects exhibited greater methylation, except for the gene MTHFR where there were no differences. Only the alternate alleles of MTHFR showed a significantly different methylation status in those without cardiopathy. (4) Conclusions: The MTHFR and AXIN genes were hypermethylated in the control group; however, only the alternate alleles of MTHFR (rs1801133 and rs1801131) showed a significantly different methylation status. Full article

Noonan syndrome (NS) and related Noonan syndrome with multiple lentigines (NSML) contribute to the pathogenesis of human diseases in the RASopathy family. This family of genetic disorders constitute one of the largest groups of developmental disorders with variable penetrance and severity, associated with distinctive congenital disabilities, including facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental retardation, and tumor predisposition. NS was first clinically described decades ago, and several genes have since been identified, providing a molecular foundation to understand their physiopathology and identify targets for therapeutic strategies. These genes encode proteins that participate in, or regulate, RAS/MAPK signalling. The RAS pathway regulates cellular metabolism by controlling mitochondrial homeostasis, dynamics, and energy production; however, little is known about the role of mitochondrial metabolism in NS and NSML. This manuscript comprehensively reviews the most frequently mutated genes responsible for NS and NSML, covering their role in the current knowledge of cellular signalling pathways, and focuses on the pathophysiological outcomes on mitochondria and energy metabolism. Full article

In our experience, the Santulli procedure (SP) can improve bowel recovery in congenital intestinal malformations, necrotizing enterocolitis (NEC), and bowel perforation. All cases managed at our institution using SP between 2012 and 2017 were included in this study. Forty-one patients underwent SP (median age: 39 (0–335) days, median weight: 2987 (1400–8100) g) for intestinal atresia (51%, two gastroschisis), NEC (29%), midgut volvulus (10%), Hirschsprung’s disease (5%), or bowel perforation (5%), with at least one intestinal suture below the Santulli in 10% of cases. The SP was performed as a primary procedure (57%) or as a double-ileostomy reversal. Anal-stool passing occurred within a median of 9 (2–36) days for 95% of patients, regardless of the diversion level or the underlying disease. All three patients requiring repeated surgery for Santulli dysfunction had presented with stoma prolapse (p < 0.01). Stoma closure was performed after a median of 45 (14–270) days allowing efficient transit after a median of 2 (1–6) days. After a median follow-up of 2.9 (0.7–7.2) years, two patients died (cardiopathy and brain hemorrhage), full oral intake had been achieved in 90% of patients, and all survivors had normal bowel movement. Whether used as primary or secondary surgery, the SP allows rapid recovery of intestinal motility and function. Full article

Nance-Horan syndrome (NHS) is a rare X-linked developmental disorder caused mainly by loss of function variants in the NHS gene. NHS is characterized by congenital cataracts, dental anomalies, and distinctive facial features, and a proportion of the affected individuals also present intellectual disability and congenital cardiopathies. Despite identification of at least 40 distinct hemizygous variants leading to NHS, genotype-phenotype correlations remain largely elusive. In this study, we describe a Sicilian family affected with congenital cataracts and dental anomalies and diagnosed with NHS by whole-exome sequencing (WES). The affected boy from this family presented a late regression of cognitive, motor, language, and adaptive skills, as well as broad behavioral anomalies. Furthermore, brain imaging showed corpus callosum anomalies and periventricular leukoencephalopathy. We expand the phenotypic and mutational NHS spectrum and review potential disease mechanisms underlying the central neurological anomalies and the potential neurodevelopmental features associated with NHS. Full article

Objective, the application of genomic sequencing in clinical practice has allowed us to appreciate the contribution of co-occurring pathogenic variants to complex and unclassified clinical phenotypes. Besides the clinical relevance, these findings have provided evidence of previously unrecognized functional links between genes in the context of developmental processes and physiology. Patients and Methods, a 5-year-old patient showing an unclassified phenotype characterized by developmental delay, speech delay, peculiar behavioral features, facial dysmorphism and severe cardiopathy was analyzed by trio-based whole exome sequencing (WES) analysis to identify the genomic events underlying the condition. Results, two co-occurring heterozygous truncating variants in CNOT3 and SMAD6 were identified. Heterozygous loss-of-function variants in CNOT3, encoding a subunit of the CCR4-NOT protein complex, have recently been reported to cause a syndromic condition known as intellectual developmental disorder with speech delay, autism and dysmorphic facies (IDDSADF). Enrichment of rare/private variants in the SMAD6 gene, encoding a protein negatively controlling transforming growth factor β/bone morphogenetic protein (TGFB/BMP) signaling, has been described in association with a wide spectrum of congenital heart defects. We dissected the contribution of individual variants to the complex clinical manifestations and profiled a previously unappreciated set of facial features and signs characterizing IDDSADF. Conclusions, two concomitant truncating variants in CNOT3 and SMAD6 are the cause of the combination of features documented in the patient resulting in the unique multisystem neurodevelopmental condition. These findings provide evidence for a functional link between the CCR4-NOT complex and TGFB/BMP signaling in processes controlling cardiac development. Finally, the present revision provides evidence that IDDSADF is characterized by a distinctive facial gestalt. Full article