Organogenesis involves integration of diverse cell types; dysregulation of cell-type-specific gene networks results in birth defects, which affect 5% of live births. Congenital heart defects are the ...most common malformations, and result from disruption of discrete subsets of cardiac progenitor cells
, but the transcriptional changes in individual progenitors that lead to organ-level defects remain unknown. Here we used single-cell RNA sequencing to interrogate early cardiac progenitor cells as they become specified during normal and abnormal cardiogenesis, revealing how dysregulation of specific cellular subpopulations has catastrophic consequences. A network-based computational method for single-cell RNA-sequencing analysis that predicts lineage-specifying transcription factors
identified Hand2 as a specifier of outflow tract cells but not right ventricular cells, despite the failure of right ventricular formation in Hand2-null mice
. Temporal single-cell-transcriptome analysis of Hand2-null embryos revealed failure of outflow tract myocardium specification, whereas right ventricular myocardium was specified but failed to properly differentiate and migrate. Loss of Hand2 also led to dysregulation of retinoic acid signalling and disruption of anterior-posterior patterning of cardiac progenitors. This work reveals transcriptional determinants that specify fate and differentiation in individual cardiac progenitor cells, and exposes mechanisms of disrupted cardiac development at single-cell resolution, providing a framework for investigating congenital heart defects.
Congenital heart disease is the most common congenital disorder in newborns. Advances in cardiovascular medicine and surgery have enabled most patients to reach adulthood. Unfortunately, prolonged ...survival has been achieved at a cost, as many patients suffer late complications, of which heart failure and arrhythmias are the most prominent. Accordingly, these patients need frequent follow-up by physicians with specific knowledge in the field of congenital heart disease. However, planning of care for this population is difficult, because the number of patients currently living with congenital heart disease is difficult to measure. Birth prevalence estimates vary widely according to different studies, and survival rates have not been well recorded. Consequently, the prevalence of congenital heart disease is unclear, with estimates exceeding the number of patients currently seen in cardiology clinics. New developments continue to influence the size of the population of patients with congenital heart disease. Prenatal screening has led to increased rates of termination of pregnancy. Improved management of complications has changed the time and mode of death caused by congenital heart disease. Several genetic and environmental factors have been shown to be involved in the etiology of congenital heart disease, although this knowledge has not yet led to the implementation of preventative measures. In this Review, we give an overview of the etiology, birth prevalence, current prevalence, mortality, and complications of congenital heart disease.
This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart ...Association scientific statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes. Recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies are provided. Insights into new research with congenital heart disease models, including genetically manipulated animals such as mice, chicks, and zebrafish, as well as human induced pluripotent stem cell-based approaches are provided to allow an understanding of how future research breakthroughs for congenital heart disease are likely to happen. It is anticipated that this review will provide a large range of health care-related personnel, including pediatric cardiologists, pediatricians, adult cardiologists, thoracic surgeons, obstetricians, geneticists, genetic counselors, and other related clinicians, timely information on the genetic aspects of congenital heart disease. The objective is to provide a comprehensive basis for interdisciplinary care for those with congenital heart disease.
To update the congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency clinical practice guideline published by the Endocrine Society in 2010.
The writing committee presents updated ...best practice guidelines for the clinical management of congenital adrenal hyperplasia based on published evidence and expert opinion with added considerations for patient safety, quality of life, cost, and utilization.
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► Mainly Toxoplasma gondii, Trypanosoma cruzi and Plasmodium parasites induce congenital infections. ► These congenital infections are often asymptomatic at birth and remain ...undetected. ► Congenital infections with T. gondii and T. cruzi can have severe outcomes. ► Plasmodium congenital infections seem frequently self-cured.
This review defines the concepts of maternal–fetal (congenital) and vertical transmissions (mother-to-child) of pathogens and specifies the human parasites susceptible to be congenitally transferred. It highlights the epidemiological features of this transmission mode for the three main congenital parasitic infections due to Toxoplasma gondii, Trypanosoma cruzi and Plasmodium sp. Information on the possible maternal–fetal routes of transmission, the placental responses to infection and timing of parasite transmission are synthesized and compared. The factors susceptible to be involved in parasite transmission and development of congenital parasitic diseases, such as the parasite genotypes, the maternal co-infections and parasitic load, the immunological features of pregnant women and the capacity of some fetuses/neonates to overcome their immunological immaturity to mount an immune response against the transmitted parasites are also discussed and compared. Analysis of clinical data indicates that parasitic congenital infections are often asymptomatic, whereas symptomatic newborns generally display non-specific symptoms. The long-term consequences of congenital infections are also mentioned, such as the imprinting of neonatal immune system and the possible trans-generational transmission. The detection of infection in pregnant women is mainly based on standard serological or parasitological investigations. Amniocentesis and cordocentesis can be used for the detection of some fetal infections. The neonatal infection can be assessed using parasitological, molecular or immunological methods; the place of PCR in such neonatal diagnosis is discussed. When such laboratory diagnosis is not possible at birth or in the first weeks of life, standard serological investigations can also be performed 8–10 months after birth, to avoid detection of maternal transmitted antibodies. The specific aspects of treatment of T. gondii, T. cruzi and Plasmodium congenital infections are mentioned. The possibilities of primary and secondary prophylaxes, as well as the available WHO corresponding recommendations are also presented.
SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with ...hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably β-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders.
Critical congenital heart defects (CCHDs) are potentially life-threatening malformations that remain a significant cause of neonatal mortality and morbidity. Failure to diagnose these conditions ...shortly after birth may result in acute cardiovascular collapse and death. The identification of CCHDs by routine newborn clinical examination is routine in many countries, but consistently misses over a third of cases, and, although antenatal ultrasound screening can be very effective in early diagnosis, the provision and accuracy of ultrasound screening is highly variable. As most CCHDs present with mild cyanosis (hypoxaemia), which is frequently clinically undetectable, pulse oximetry is a rapid, simple, painless method of accurately identifying hypoxaemia, which has gained popularity as a screen for CCHD. This Special Issue of the International Journal of Neonatal Screening, devoted to "Neonatal Screening for Critical Congenital Heart Defects (CCHDs)", will consider the evidence for CCHD screening with pulse oximetry, the acceptability and cost-effectiveness of this intervention, the additional non-cardiac conditions which it may also identify, and international experiences of introducing CCHD screening across the globe.
Congenital heart disease (CHD) is common in trisomy 13 (T13) and trisomy 18 (T18), but surgical repair has not been offered in most centers. Data on outcomes of congenital heart surgery (CHS) for T13 ...and T18 are lacking. We sought to determine the impact of CHS on in-hospital mortality in T13 and T18.
Data from the 2004 to 2015 Pediatric Health Information System database were used to identify inpatients with T13 or T18 and CHD. Data were restricted to newborns with T13 or T18 admitted at ≤14 days of age. Hospital readmissions were examined to analyze longer-term in-hospital mortality. In-hospital mortality and length of stay were compared between infants with and without CHD and with and without CHS.
The study cohort included 1020 infants with T18 and 648 infants with T13. CHD was present in 91% of infants with T18 and 86% of infants with T13. CHS was performed in 7% of each group. In-hospital mortality was decreased in those who underwent CHS (64% lower in T18
<.001; 45% lower in T13
= .003) and remained decreased throughout the 24 months of follow-up. In-hospital mortality was decreased in infants with higher weight, female sex, and older age at admission.
CHS is associated with decreased in-hospital mortality in T18 and T13. These results suggest CHS may be beneficial in select cases.
Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We ...investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP).
Three population-based EUROCAT congenital anomaly registries- Norway (2004-2010), Wales (2000-2010) and Funen, Denmark (2000-2010)-were linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 0.26% vs. 865/506,155 0.17% OR 1.50, 1.06-2.11), and the composite adverse outcome of 'anomaly or stillbirth' (473/12962, 3.65% vs. 15829/506,155, 3.13%, OR 1.13, 1.03-1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09% 400/12,962 vs. 2.67% 13,536/506,155 OR 1.09, 0.99-1.21). Adjusting for socio-economic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.12-1.97) was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression.
The additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health importance, justifying modifications to preconception care.
Holt-Oram syndrome (HOS) is a rare, autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. A wide spectrum of TBX5 mutations have been reported previously, most resulting in a ...null allele leading to haploinsufficiency. TBX5 gene duplications have been previously reported in association with typical and atypical HOS phenotypes. Ulnar-Mammary syndrome (UMS) is a distinct rare, autosomal dominant condition caused by mutations in the TBX3 gene. TBX5 and TBX3 are physically linked in cis on human chromosome 12 and contiguous chromosome 12q24 deletions comprising both TBX5 and TBX3 genes have been previously reported but to our knowledge, duplications have never been described. We report on a large German family with at least 17 affected individuals over 6 generations bearing a duplication at 12q24.21 identified on array-CGH comprising both TBX5 and TBX3 genes. Affected patients are presenting with HOS and UMS symptoms, consisting of variable limb anomalies involving the radial and the ulnar rays and cardiac findings such as congenital heart defects, persistent arterial duct or aortic stenosis, and non-classical symptoms, such as supernumerary nipples and cardiomyopathy. Fluorescence in situ hybridisation confirmed a tandem duplication at the 12q24.21 locus. This is the first report of a contiguous TBX3/TBX5 duplication associated with HOS/UMS phenotype.
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