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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 -
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 -
Radiologia Brasileira 2018
PubMed: 30369671
DOI: 10.1590/0100-3984.2017.0063 -
Indian Journal of Thoracic and... Jan 2021Heterotaxy syndrome (HS) constitutes a spectrum of anomalies arising from embryological errors that result in abnormalities of lateralization involving thoraco-abdominal... (Review)
Review
Heterotaxy syndrome (HS) constitutes a spectrum of anomalies arising from embryological errors that result in abnormalities of lateralization involving thoraco-abdominal viscera and culminate in loss of normal asymmetric arrangement of these organs. Besides the unique challenges involved in planning and execution of surgical procedures aimed at correction or palliation of these anomalies, they have the potential to cause profound physiological and immunological consequences in the individual patient due to their cardiac and extra-cardiac manifestations. This article aims to review the literature on this rare and extraordinary subset of developmental anomalies with the intention of familiarizing the reader on the modes of presentation, manifestations, and the variations thereof while dealing with this anomaly. In our institutional experience with HS, 75 consecutive patients were seen between January 2011 and September 2018. Of these, 48 (64%) were confirmed to have isomerism of right atrial appendages (IRAA) and the rest had isomerism of left atrial appendages (ILAA). The cardiac and extra-cardiac manifestations of these patients were listed out. Fifty-four patients (34 with IRAA and 20 with ILAA) underwent 83 surgical procedures. While 49 patients were palliated on the univentricular pathway, 5 underwent biventricular repair. The in-hospital mortality was 7 (13%) in both groups combined (5 for patients with IRAA and 2 for ILAA). In conclusion, the surgical management of HS is associated with satisfactory outcomes in current era.
PubMed: 33603285
DOI: 10.1007/s12055-020-00935-y -
Progress in Pediatric Cardiology Sep 2017Left ventricular noncompaction cardiomyopathy (LVNC) is characterized by compact and trabecular layers of the left ventricular myocardium. This cardiomyopathy may occur...
Left ventricular noncompaction cardiomyopathy (LVNC) is characterized by compact and trabecular layers of the left ventricular myocardium. This cardiomyopathy may occur with congenital heart disease (CHD). Single cases document co-occurrence of LVNC and heterotaxy, but no data exist regarding the prevalence of this association. This study sought to determine whether a non-random association of LVNC and heterotaxy exists by evaluating the prevalence of LVNC in patients with heterotaxy. In a retrospective review of the Indiana Network for Patient Care, we identified 172 patients with heterotaxy (69 male, 103 female). Echocardiography and cardiac magnetic resonance imaging results were independently reviewed by two cardiologists to ensure reproducibility of LVNC. A total of 13/172 (7.5%) patients met imaging criteria for LVNC. The CHD identified in this subgroup included atrioventricular septal defects [11], dextrocardia [10], systemic and pulmonary venous return abnormalities [7], and transposition of the great arteries [5]. From this subgroup, 61% ( = 8) of the patients developed arrhythmias; and 61% ( = 8) required medical management for chronic heart failure. This study indicates that LVNC has increased prevalence among patients with heterotaxy when compared to the general population (0.014-1.3%) suggesting possible common genetic mechanisms. Interestingly, mice with a loss of function of or genes showed abnormal compaction of the ventricles, anomalies in cardiac looping, and septation defects in previous studies. Recognition of the association between LVNC and heterotaxy is important for various reasons. First, the increased risk of arrhythmias demonstrated in our population. Secondly, theoretical risk of thromboembolic events remains in any LVNC population. Finally, many patients with heterotaxy undergo cardiac surgery (corrective and palliative) and when this is associated with LVNC, patients should be presumed to incur a higher peri-operative morbidity based on previous studies. Further research will continue to determine long-term and to corroborate genetic pathways.
PubMed: 29445263
DOI: 10.1016/j.ppedcard.2017.06.007 -
Cureus Apr 2021Heterotaxy syndrome implies a discordance between placement of thoracic organs with respect to abdominal organs. A large number of these have associated congenital heart...
Heterotaxy syndrome implies a discordance between placement of thoracic organs with respect to abdominal organs. A large number of these have associated congenital heart defects. This syndrome is unique as every patient is different and can have any permutation and combination of symptoms. In our case, the five-year-old male child presented with complaints of abdominal distension, fever, and bluish discoloration of limbs with even mild exertion. Radiological evaluation was diagnosed with a large atrial septal defect, cardiomegaly, partial pulmonary venous circulation, multiple small spleens on the right side of body, a large midline liver, malrotated bowel, inferiorly displaced kidneys, and two hemiazygos veins. The echocardiography and electrocardiogram too were consistent with atrial septal defect and right ventricular strain pattern. The reasons for this highly variable pattern are rooted in the genetically complicated process of lateralization with a strong link to the copy number variations. Due to the variable patterns, it is more efficient to report all the findings utilizing a step-by-step process of commenting on each and every individual organ, instead of classifying them under different categories based on atrial isomerism. This is important as any other way of classification predisposes to a certain bias.
PubMed: 34094731
DOI: 10.7759/cureus.14766 -
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