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Circulation Nov 2018This 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... (Review)
Review
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.
Topics: American Heart Association; Aneuploidy; DNA Copy Number Variations; Down Syndrome; Genetic Variation; Heart Defects, Congenital; Humans; Polymorphism, Single Nucleotide; United States
PubMed: 30571578
DOI: 10.1161/CIR.0000000000000606 -
JACC. Basic To Translational Science Apr 2020Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify...
Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins , , and and the regulators of small GTPase signaling and are critical to cardiac development.
PubMed: 32368696
DOI: 10.1016/j.jacbts.2020.01.012 -
Advances in Experimental Medicine and... 2018Mutation of ZIC3 causes X-linked heterotaxy, a syndrome in which the laterality of internal organs is disrupted. Analysis of model organisms and gene expression during... (Review)
Review
Mutation of ZIC3 causes X-linked heterotaxy, a syndrome in which the laterality of internal organs is disrupted. Analysis of model organisms and gene expression during early development suggests ZIC3-related heterotaxy occurs due to defects at the earliest stage of left-right axis formation. Although there are data to support abnormalities of the node and cilia as underlying causes, it is unclear at the molecular level why loss of ZIC3 function causes such these defects. ZIC3 has putative roles in a number of developmental signalling pathways that have distinct roles in establishing the left-right axis. This complicates the understanding of the mechanistic basis of Zic3 in early development and left-right patterning. Here we summarise our current understanding of ZIC3 function and describe the potential role ZIC3 plays in important signalling pathways and their links to heterotaxy.
Topics: Animals; Dextrocardia; Genetic Diseases, X-Linked; Heterotaxy Syndrome; Homeodomain Proteins; Humans; Mutation; Signal Transduction; Transcription Factors
PubMed: 29442328
DOI: 10.1007/978-981-10-7311-3_15 -
Clinics in Chest Medicine Sep 2016Primary ciliary dyskinesia (PCD) is a recessive genetically heterogeneous disorder of motile cilia with chronic otosinopulmonary disease and organ laterality defects in... (Review)
Review
Primary ciliary dyskinesia (PCD) is a recessive genetically heterogeneous disorder of motile cilia with chronic otosinopulmonary disease and organ laterality defects in ∼50% of cases. The prevalence of PCD is difficult to determine. Recent diagnostic advances through measurement of nasal nitric oxide and genetic testing has allowed rigorous diagnoses and determination of a robust clinical phenotype, which includes neonatal respiratory distress, daily nasal congestion, and wet cough starting early in life, along with organ laterality defects. There is early onset of lung disease in PCD with abnormal airflow mechanics and radiographic abnormalities detected in infancy and early childhood.
Topics: Administration, Inhalation; Administration, Intranasal; Adrenal Cortex Hormones; Anti-Bacterial Agents; Breath Tests; Chronic Disease; Cilia; Cough; Endoscopy; Genetic Testing; Heterotaxy Syndrome; Humans; Kartagener Syndrome; Middle Ear Ventilation; Nasal Lavage; Nitric Oxide; Otitis Media; Phenotype; Respiratory Distress Syndrome, Newborn; Saline Solution, Hypertonic; Sinusitis; Situs Inversus
PubMed: 27514592
DOI: 10.1016/j.ccm.2016.04.008 -
Orphanet Journal of Rare Diseases Sep 2022Heterotaxy (HTX) is a rare condition of abnormal thoraco-abdominal organ arrangement across the left-right axis of the body. The pathogenesis of HTX includes a... (Review)
Review
Heterotaxy (HTX) is a rare condition of abnormal thoraco-abdominal organ arrangement across the left-right axis of the body. The pathogenesis of HTX includes a derangement of the complex signaling at the left-right organizer early in embryogenesis involving motile and non-motile cilia. It can be inherited as a single-gene disorder, a phenotypic feature of a known genetic syndrome or without any clear genetic etiology. Most patients with HTX have complex cardiovascular malformations requiring surgical intervention. Surgical risks are relatively high due to several serious comorbidities often seen in patients with HTX. Asplenia or functional hyposplenism significantly increase the risk for sepsis and therefore require antimicrobial prophylaxis and immediate medical attention with fever. Intestinal rotation abnormalities are common among patients with HTX, although volvulus is rare and surgical correction carries substantial risk. While routine screening for intestinal malrotation is not recommended, providers and families should promptly address symptoms concerning for volvulus and biliary atresia, another serious morbidity more common among patients with HTX. Many patients with HTX have chronic lung disease and should be screened for primary ciliary dyskinesia, a condition of respiratory cilia impairment leading to bronchiectasis. Mental health and neurodevelopmental conditions need to be carefully considered among this population of patients living with a substantial medical burden. Optimal care of children with HTX requires a cohesive team of primary care providers and experienced subspecialists collaborating to provide compassionate, standardized and evidence-based care. In this statement, subspecialty experts experienced in HTX care and research collaborated to provide expert- and evidence-based suggestions addressing the numerous medical issues affecting children living with HTX.
Topics: Anti-Bacterial Agents; Bronchiectasis; Child; Humans; Intestinal Volvulus
PubMed: 36085154
DOI: 10.1186/s13023-022-02515-2 -
Korean Circulation Journal May 2011Heterotaxy is defined as an abnormality where the internal thoraco-abdominal organs demonstrate abnormal arrangement across the left-right axis of the body. This broad...
Heterotaxy is defined as an abnormality where the internal thoraco-abdominal organs demonstrate abnormal arrangement across the left-right axis of the body. This broad term includes patients with a wide variety of very complex cardiac lesions. Patients with heterotaxy can be stratified into the subsets of asplenia syndrome and polysplenia syndrome, or the subsets of heterotaxy with isomerism of the right atrial appendages and heterotaxy with isomerism of the left atrial appendages. Treatment of patients with isomerism is determined by the nature and severity of the associated cardiac and extracardiac lesions. Most cardiac operations for patients with isomerism are palliative in nature, since normal anatomy is rarely achieved and mortality rates remain high for patients with heterotaxy syndrome. Patients with left isomerism in general have less severe cardiac malformations than those with right isomerism and, hence, more chance of biventricular repair. For almost all patients with right isomerism, and for many with left isomerism, biventricular repair will not be feasible, and all palliative protocols are then staging procedures prior to a Fontan-type repair. Recent advances in medical management, and improvements in surgical techniques have resulted in improved survival for these patients, and the surgical outcomes are comparable to those with Fontan circulation irrespective of the presence or absence of heterotaxy.
PubMed: 21731561
DOI: 10.4070/kcj.2011.41.5.227 -
The Journal of Thoracic and... Jun 2015
Topics: Abnormalities, Multiple; Cardiac Surgical Procedures; Female; Heterotaxy Syndrome; Humans; Male
PubMed: 25752369
DOI: 10.1016/j.jtcvs.2015.01.039 -
Children (Basel, Switzerland) May 2021In this paper, the author enumerates cardiac defects with a functionally single ventricle, summarizes single ventricle physiology, presents a summary of management... (Review)
Review
In this paper, the author enumerates cardiac defects with a functionally single ventricle, summarizes single ventricle physiology, presents a summary of management strategies to address the single ventricle defects, goes over the steps of staged total cavo-pulmonary connection, cites the prevalence of inter-stage mortality, names the causes of inter-stage mortality, discusses strategies to address the inter-stage mortality, reviews post-Fontan issues, and introduces alternative approaches to Fontan circulation.
PubMed: 34073809
DOI: 10.3390/children8060441 -
Human Molecular Genetics Jul 2023FOXJ1 is expressed in ciliated cells of the airways, testis, oviduct, central nervous system and the embryonic left-right organizer. Ablation or targeted mutation of...
FOXJ1 is expressed in ciliated cells of the airways, testis, oviduct, central nervous system and the embryonic left-right organizer. Ablation or targeted mutation of Foxj1 in mice, zebrafish and frogs results in loss of ciliary motility and/or reduced length and number of motile cilia, affecting the establishment of the left-right axis. In humans, heterozygous pathogenic variants in FOXJ1 cause ciliopathy leading to situs inversus, obstructive hydrocephalus and chronic airway disease. Here, we report a novel truncating FOXJ1 variant (c.784_799dup; p.Glu267Glyfs*12) identified by clinical exome sequencing from a patient with isolated congenital heart defects (CHD) which included atrial and ventricular septal defects, double outlet right ventricle (DORV) and transposition of the great arteries. Functional experiments show that FOXJ1 c.784_799dup; p.Glu267Glyfs*12, unlike FOXJ1, fails to induce ectopic cilia in frog epidermis in vivo or to activate the ADGB promoter, a downstream target of FOXJ1 in cilia, in transactivation assays in vitro. Variant analysis of patients with heterotaxy or heterotaxy-related CHD indicates that pathogenic variants in FOXJ1 are an infrequent cause of heterotaxy. Finally, we characterize embryonic-stage CHD in Foxj1 loss-of-function mice, demonstrating randomized heart looping. Abnormal heart looping includes reversed looping (dextrocardia), ventral looping and no looping/single ventricle hearts. Complex CHDs revealed by histological analysis include atrioventricular septal defects, DORV, single ventricle defects as well as abnormal position of the great arteries. These results indicate that pathogenic variants in FOXJ1 can cause isolated CHD.
Topics: Humans; Male; Forkhead Transcription Factors; Heart Atria; Heart Defects, Congenital; Heart Septal Defects; Heterotaxy Syndrome; Transposition of Great Vessels
PubMed: 37158461
DOI: 10.1093/hmg/ddad065 -
Journal of Cardiovascular Computed... 2013Heterotaxy and situs abnormalities describe an abnormal arrangement of visceral organs in the thoracoabdominal cavity across the normal left-right axis of the body. It... (Review)
Review
Heterotaxy and situs abnormalities describe an abnormal arrangement of visceral organs in the thoracoabdominal cavity across the normal left-right axis of the body. It is associated with a high occurrence of congenital heart and abdominal defects, including anomalous pulmonary venous connections, systemic venous abnormalities, asplenia, and intestinal malrotation. Without proper diagnosis and surgical intervention, the prognosis of patients with heterotaxy syndrome and associated congenital defects is extremely poor. Complex intracardiac and extracardiac lesions are common in heterotaxy and can be difficult to assess by echocardiography. CT angiography (CTA) is a useful tool in this setting to accurately assess intracardiac and extracardiac abnormalities in this population for medical or surgical management. The intention of this pictorial essay is to review the most common cardiovascular defects involved with heterotaxy syndrome in addition to emphasizing the utility of CTA in the identification and classification of anomalies seen in these patients. This review briefly defines most common terminology used in situs abnormalities as well as presents CT images and 3-dimensional reconstructions of common anomalies associated with situs abnormalities. In summary, this review should prepare radiologists and pediatric cardiologists to describe heterotaxy and situs abnormalities in addition to recognizing the utility of CTA in these patients.
Topics: Abnormalities, Multiple; Child; Coronary Angiography; Heart Defects, Congenital; Heterotaxy Syndrome; Humans; Infant, Newborn; Tomography, X-Ray Computed
PubMed: 24331937
DOI: 10.1016/j.jcct.2013.11.008