The physiology of the fetus is fundamentally different from the neonate, with both structural and functional distinctions. The fetus is well-adapted to the relatively hypoxemic intrauterine ...environment. The transition from intrauterine to extrauterine life requires rapid, complex, and well-orchestrated steps to ensure neonatal survival. This article explains the intrauterine physiology that allows the fetus to survive and then reviews the physiologic changes that occur during the transition to extrauterine life. Asphyxia fundamentally alters the physiology of transition and necessitates a thoughtful approach in the management of affected neonates.
The application of next-generation sequencing to study congenital heart disease (CHD) is increasingly providing new insights into the causes and mechanisms of this prevalent birth anomaly. ...Whole-exome sequencing analysis identifies damaging gene variants altering single or contiguous nucleotides that are assigned pathogenicity based on statistical analyses of families and cohorts with CHD, high expression in the developing heart and depletion of damaging protein-coding variants in the general population. Gene classes fulfilling these criteria are enriched in patients with CHD and extracardiac abnormalities, evidencing shared pathways in organogenesis. Developmental single-cell transcriptomic data demonstrate the expression of CHD-associated genes in particular cell lineages, and emerging insights indicate that genetic variants perturb multicellular interactions that are crucial for cardiogenesis. Whole-genome sequencing analyses extend these observations, identifying non-coding variants that influence the expression of genes associated with CHD and contribute to the estimated ~55% of unexplained cases of CHD. These approaches combined with the assessment of common and mosaic genetic variants have provided a more complete knowledge of the causes and mechanisms of CHD. Such advances provide knowledge to inform the clinical care of patients with CHD or other birth defects and deepen our understanding of the complexity of human development. In this Review, we highlight known and candidate CHD-associated human genes and discuss how the integration of advances in developmental biology research can provide new insights into the genetic contributions to CHD.
MicroRNAs (miRNAs) are regulators of myriad cellular events, but evidence for a single miRNA that can efficiently differentiate multipotent stem cells into a specific lineage or regulate direct ...reprogramming of cells into an alternative cell fate has been elusive. Here we show that miR-145 and miR-143 are co-transcribed in multipotent murine cardiac progenitors before becoming localized to smooth muscle cells, including neural crest stem-cell-derived vascular smooth muscle cells. miR-145 and miR-143 were direct transcriptional targets of serum response factor, myocardin and Nkx2-5 (NK2 transcription factor related, locus 5) and were downregulated in injured or atherosclerotic vessels containing proliferating, less differentiated smooth muscle cells. miR-145 was necessary for myocardin-induced reprogramming of adult fibroblasts into smooth muscle cells and sufficient to induce differentiation of multipotent neural crest stem cells into vascular smooth muscle. Furthermore, miR-145 and miR-143 cooperatively targeted a network of transcription factors, including Klf4 (Kruppel-like factor 4), myocardin and Elk-1 (ELK1, member of ETS oncogene family), to promote differentiation and repress proliferation of smooth muscle cells. These findings demonstrate that miR-145 can direct the smooth muscle fate and that miR-145 and miR-143 function to regulate the quiescent versus proliferative phenotype of smooth muscle cells.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Midazolam is a benzodiazepine sedative used in NICUs. Because benzodiazepine's effects include respiratory depression and potential detrimental developmental effects, minimizing exposure could ...benefit neonates. Dexmedetomidine is routinely used for sedation in older pediatric populations. We implemented a quality improvement initiative with the aim of decreasing midazolam infusions by 20% through use of dexmedetomidine.
A multidisciplinary committee created a sedation guideline that included standardized dexmedetomidine dosing escalation and weaning. Baseline data collection occurred from January 2015 to February 2018, with intervention from March 2018 to December 2019. Percentage of sedation episodes with dexmedetomidine initiated was followed as a process measure. Outcomes measures were percentage of eligible infants receiving midazolam infusions and midazolam-free days per sedation episode. Bradycardia with dexmedetomidine, unplanned extubation rates, and morphine dosage were monitored as balancing measures.
Our study included 434 episodes of sedation in 386 patients. Dexmedetomidine initiation increased from 18% to 49%. The intervention was associated with a significant reduction in midazolam initiation by 30%, from 95% to 65%, with special cause variation on statistical process control chart analysis. Midazolam-free days per sedation episode increased from 0.3 to 2.2 days, and patients receiving dexmedetomidine had lower midazolam doses (1.3 mg/kg per day versus 2.2 mg/kg per day,
= 5.97 × 10
). Bradycardia requiring discontinuation of dexmedetomidine, unplanned extubation rates, and morphine doses were unchanged.
Implementation of a quality improvement initiative was successful in reducing the percentage of patients receiving midazolam infusions and increased midazolam-free days per sedation episode, revealing an overall reduction in benzodiazepine exposure while maintaining adequate sedation.
Congenital heart disease (CHD) is the most common birth anomaly, affecting almost 1% of infants. Neurodevelopmental delay is the most common extracardiac feature in people with CHD. Many factors may ...contribute to neurodevelopmental risk, including genetic factors, CHD physiology, and the prenatal/postnatal environment. Damaging variants are most highly enriched among individuals with extracardiac anomalies or neurodevelopmental delay in addition to CHD, indicating that genetic factors have an impact beyond cardiac tissues in people with CHD. Potential sources of genetic risk include large deletions or duplications that affect multiple genes, such as 22q11 deletion syndrome, single genes that alter both heart and brain development, such as CHD7, and common variants that affect neurodevelopmental resiliency, such as APOE. Increased use of genome-sequencing technologies in studies of neurodevelopmental outcomes in people with CHD will improve our ability to detect relevant genes and variants. Ultimately, such knowledge can lead to improved and more timely intervention of learning support for affected children.
La cardiopathie congénitale (CC) est la malformation néonatale la plus fréquente. Elle touche près de 1 % des nouveau-nés. Le retard neurodéveloppemental constitue la caractéristique extracardiaque la plus répandue chez les sujets atteints de CC. De nombreux facteurs peuvent contribuer au risque neurodéveloppemental, notamment des facteurs génétiques, la physiologie de la CC et l’environnement pré ou postnatal. Les variantes dommageables constituent un fardeau plus lourd encore chez les sujets touchés par des anomalies extracardiaques ou un retard neurodéveloppemental en plus de la CC, ce qui indique que les facteurs génétiques ont un effet au-delà des tissus cardiaques en présence d’une CC. Les sources potentielles de risque génétique comprennent des délétions ou des duplications importantes qui affectent plusieurs gènes, comme le syndrome de délétion 22q11, des gènes uniques qui modifient le développement du cœur et du cerveau, comme CHD7, et des variantes communes qui nuisent à la résilience neurodéveloppementale, comme APOE. L’utilisation accrue des technologies de séquençage du génome dans le cadre des études sur les effets neurodéveloppementaux observés chez les sujets atteints de CC améliorera notre capacité à détecter les gènes et les variantes en cause. En fin de compte, les connaissances acquises peuvent permettre d’intervenir de meilleure façon et plus rapidement en matière d’aide à l’apprentissage auprès des enfants touchés.
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There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo ...single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown. Quantifying this risk would clarify the clinical significance of delayed paternity. Using parent-child trio whole-exome-sequencing data, we estimate the relationship between paternal-age-related dnSNVs and risk for five disorders: autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability and schizophrenia (SCZ). Using Danish registry data, we investigate whether epidemiologic associations between each disorder and older fatherhood are consistent with the estimated role of dnSNVs. We find that paternal-age-related dnSNVs confer a small amount of risk for these disorders. For ASD and SCZ, epidemiologic associations with delayed paternity reflect factors that may not increase with age.
Although DNA methylation is the best characterized epigenetic mark, the mechanism by which it is targeted to specific regions in the genome remains unclear. Recent studies have revealed that local ...DNA methylation profiles might be dictated by cis-regulatory DNA sequences that mainly operate via DNA-binding factors. Consistent with this finding, we have recently shown that disruption of CTCF-binding sites by rare single nucleotide variants (SNVs) can underlie cis-linked DNA methylation changes in patients with congenital anomalies. These data raise the hypothesis that rare genetic variation at transcription factor binding sites (TFBSs) might contribute to local DNA methylation patterning. In this work, by combining blood genome-wide DNA methylation profiles, whole genome sequencing-derived SNVs from 247 unrelated individuals along with 133 predicted TFBS motifs derived from ENCODE ChIP-Seq data, we observed an association between the disruption of binding sites for multiple TFs by rare SNVs and extreme DNA methylation values at both local and, to a lesser extent, distant CpGs. While the majority of these changes affected only single CpGs, 24% were associated with multiple outlier CpGs within ±1kb of the disrupted TFBS. Interestingly, disruption of functionally constrained sites within TF motifs lead to larger DNA methylation changes at nearby CpG sites. Altogether, these findings suggest that rare SNVs at TFBS negatively influence TF-DNA binding, which can lead to an altered local DNA methylation profile. Furthermore, subsequent integration of DNA methylation and RNA-Seq profiles from cardiac tissues enabled us to observe an association between rare SNV-directed DNA methylation and outlier expression of nearby genes. In conclusion, our findings not only provide insights into the effect of rare genetic variation at TFBS on shaping local DNA methylation and its consequences on genome regulation, but also provide a rationale to incorporate DNA methylation data to interpret the functional role of rare variants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains challenging. We hypothesized that genetic determinants for CHDs may lie in the protein ...interactomes of transcription factors whose mutations cause CHDs. Defining the interactomes of two transcription factors haplo-insufficient in CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the results with nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants of interactome members based on residue, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating genetic variants in heart disease.
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•GATA4:TBX5 interactome in CPs is enriched in de novo variants associated with CHD•A method for scoring interactome variants identified GLYR1 as a candidate CHD gene•GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes•The GLYR1 CHD variant disrupted interaction with GATA4 and impaired cardiogenesis
The integration of human protein-protein interactome networks of endogenous transcription factors known to be involved in cardiac malformations with the largest whole-exome-sequencing dataset of trios with congenital heart disease identified an enrichment of rare de novo variants among interactome proteins, pointing to candidate disease genes.
We evaluated genome sequencing (GS) as an alternative to multigene panel sequencing (PS) for genetic testing in dilated cardiomyopathy (DCM).
Forty-two patients with familial DCM underwent PS and GS, ...and detection rates of rare single-nucleotide variants and small insertions/deletions in panel genes were compared. Loss-of-function variants in 406 cardiac-enriched genes were evaluated, and an assessment of structural variation was performed.
GS provided broader and more uniform coverage than PS, with high concordance for rare variant detection in panel genes. GS identified all PS-identified pathogenic or likely pathogenic variants as well as two additional likely pathogenic variants: one was missed by PS due to low coverage, the other was a known disease-causing variant in a gene not included on the panel. No loss-of-function variants in the extended gene set met clinical criteria for pathogenicity. One BAG3 structural variant was classified as pathogenic.
Our data support the use of GS for genetic testing in DCM, with high variant detection accuracy and a capacity to identify structural variants. GS provides an opportunity to go beyond suites of established disease genes, but the incremental yield of clinically actionable variants is limited by a paucity of genetic and functional evidence for DCM association.
Congenital heart disease (CHD) and prematurity are leading causes of infant mortality in the United States. Infants with CHD born prematurely are often described as facing "double jeopardy" with ...vulnerability from their underlying heart disease and from organ immaturity. They endure additional complications of developing in the extrauterine environment while healing from interventions for heart disease. While morbidity and mortality for neonates with CHD have declined over the past decade, preterm neonates with CHD remain at higher risk for adverse outcomes. Less is known about their neurodevelopmental and functional outcomes. In this perspective paper, we review the prevalence of preterm birth among infants with CHD, highlight the medical complexity of these infants, and emphasize the importance of exploring outcomes beyond survival. We focus on current knowledge regarding overlaps in the mechanisms of neurodevelopmental impairment associated with CHD and prematurity and discuss future directions for improving neurodevelopmental outcomes.
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