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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 -
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 -
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 -
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 -
Animal Cells and Systems 2021Laterality defects during embryonic development underlie the aetiology of various clinical symptoms of neuropathological and cardiovascular disorders; however,...
Laterality defects during embryonic development underlie the aetiology of various clinical symptoms of neuropathological and cardiovascular disorders; however, experimental approaches to understand the underlying mechanisms are limited due to the complex organ systems of vertebrate models. Zebrafish have the ability to survive even when the heart stops beating for a while during early embryonic development and those adults with cardiac abnormalities. Therefore, we induced laterality defects and investigated the occurrence of situs solitus, situs inversus, and situs ambiguus in zebrafish development. Histopathological analysis revealed heterotaxy in both embryos and juvenile fish. Additionally, randomization of left-right asymmetry of the brain and heart in individual zebrafish embryos under artificial experimental pressure further demonstrated the advantage of transparent zebrafish embryos as an experimental tool to select or reduce the embryos with laterality defects during early embryonic development for long-term studies, including behavioural and cognitive neuroscience investigations.
PubMed: 34262656
DOI: 10.1080/19768354.2021.1931443 -
Frontiers in Cell and Developmental... 2022Vital internal organs display a left-right (LR) asymmetric arrangement that is established during embryonic development. Disruption of this LR asymmetry-or... (Review)
Review
Vital internal organs display a left-right (LR) asymmetric arrangement that is established during embryonic development. Disruption of this LR asymmetry-or laterality-can result in congenital organ malformations. (SIT) is a complete concordant reversal of internal organs that results in a low occurrence of clinical consequences. , which gives rise to Heterotaxy syndrome (HTX), is characterized by discordant development and arrangement of organs that is associated with a wide range of birth defects. The leading cause of health problems in HTX patients is a congenital heart malformation. Mutations identified in patients with laterality disorders implicate motile cilia in establishing LR asymmetry. However, the cellular and molecular mechanisms underlying SIT and HTX are not fully understood. In several vertebrates, including mouse, frog and zebrafish, motile cilia located in a "left-right organizer" (LRO) trigger conserved signaling pathways that guide asymmetric organ development. Perturbation of LRO formation and/or function in animal models recapitulates organ malformations observed in SIT and HTX patients. This provides an opportunity to use these models to investigate the embryological origins of laterality disorders. The zebrafish embryo has emerged as an important model for investigating the earliest steps of LRO development. Here, we discuss clinical characteristics of human laterality disorders, and highlight experimental results from zebrafish that provide insights into LRO biology and advance our understanding of human laterality disorders.
PubMed: 36619867
DOI: 10.3389/fcell.2022.1035513 -
The Journal of Clinical Investigation Jun 2019Motile cilia provide propulsion, and immotile ones are enriched with receptors. Both are required to establish left-right identity in the developing embryo and are also...
Motile cilia provide propulsion, and immotile ones are enriched with receptors. Both are required to establish left-right identity in the developing embryo and are also implicated in a wide range of human diseases. Abnormalities in cilial function underlie heterotaxy congenital heart disease (CHD) occurring in individuals with laterality disturbance. Mitochondrial function and cellular energetics, through mTOR and autophagy, are now linked with cilial function, revealing new mechanisms and candidate genes for syndromic human disease. In the current issue of the JCI, Burkhalter et al. ask the question: Can mitochondrial disturbances produce ciliopathy and does this explain some cases of heterotaxy?
Topics: Cilia; Ciliopathies; Heart; Heterotaxy Syndrome; Humans; Mitochondria
PubMed: 31205030
DOI: 10.1172/JCI129827 -
Translational Pediatrics Aug 2023Primary ciliary dyskinesia (PCD) is a clinically heterogeneous group of autosomal or, less frequently, X-chromosomal recessive inheritance syndrome of motile cilia...
BACKGROUND
Primary ciliary dyskinesia (PCD) is a clinically heterogeneous group of autosomal or, less frequently, X-chromosomal recessive inheritance syndrome of motile cilia dysfunction characterized by neonatal respiratory distress, oto-sino-pulmonary disease, infertility and situs inversus. Recently, type 43 PCD (CILD43, OMIM#618699) was established by autosomal-dominant loss-of-function mutations identified in Forkhead box J1 (). However, the functional validation of mutations in humans and mice has not been fully performed. Here we studied a three-generation family with heterotaxy and proband with complex congenital heart disease (CHD).
METHODS
We performed whole-exome sequencing to investigate the causative variant of this family and generated gene knock-in mice carrying the human equivalent mutation by homologous recombination. Then, microscopy analysis was used to characterize the phenotype and ciliary ultrastructure of the model. Effects of the variant on heart anomaly were preliminarily explored through transcriptome sequencing.
RESULTS
A novel heterozygous deletion variant (c.1129delC/p.Leu377Trpfs*76) of was discovered that exerts a dominant-negative effect (DNE) . Notably, both homozygous () and heterozygous () mice developed situs inversus, hydrocephalus and showed a disruption of trachea cilia structure, whereas these abnormalities were only observed in previously reported , not mice. Thus, a more severe phenotype and higher expressivity of our mouse model further indicated the DNE of this mutation. Meanwhile, several cardiomyopathy-related genes were differentially expressed in the homozygous knock-in mouse hearts, pointing to a probable function in cardiac pathology.
CONCLUSIONS
Overall, our study results showed that c.1129delC mutation in was regarded as the cause of situs inversus in this family and this mutant showed a capacity of DNE over wild-type FOXJ1, causing more serious consequences than the allelic deletion of .
PubMed: 37692537
DOI: 10.21037/tp-23-27 -
Journal of Clinical Medicine Apr 2022Congenital heart diseases (CHD) result from abnormal development of the cardiovascular system and usually involve defects in specific steps or structural components of... (Review)
Review
Congenital heart diseases (CHD) result from abnormal development of the cardiovascular system and usually involve defects in specific steps or structural components of the developing heart and vessels. The determination of left-right patterning of our body proceeds by the steps involving the leftward "nodal flow" by motile cilia in the node and molecules that are expressed only on the left side of the embryo, eventually activating the molecular pathway for the left-side specific morphogenesis. Disruption of any of these steps may result in left-right patterning defects or heterotaxy syndrome. As for the outflow tract development, neural crest cells migrate into the cardiac outflow tract and contribute to form the septum of the outflow tract that divides the embryonic single truncus arteriosus into the aortic and the pulmonary trunk. Reciprocal signaling between neural crest cells and another population of myocardial precursor cells originated from the second heart field are essential for the steps of outflow tract development. To better understand the etiology of CHD, it is important to consider what kind of CHD is caused by abnormalities in each step during the complex development of the cardiovascular system.
PubMed: 35566507
DOI: 10.3390/jcm11092381