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1.
Cereb Cortex ; 34(6)2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38836834

ABSTRACT

Congenital heart disease affects 1% of infants and is associated with impaired neurodevelopment. Right- or left-sided sulcal features correlate with executive function among people with Tetralogy of Fallot or single ventricle congenital heart disease. Studies of multiple congenital heart disease types are needed to understand regional differences. Further, sulcal pattern has not been studied in people with d-transposition of the great arteries. Therefore, we assessed the relationship between sulcal pattern and executive function, general memory, and processing speed in a meta-regression of 247 participants with three congenital heart disease types (114 single ventricle, 92 d-transposition of the great arteries, and 41 Tetralogy of Fallot) and 94 participants without congenital heart disease. Higher right hemisphere sulcal pattern similarity was associated with improved executive function (Pearson r = 0.19, false discovery rate-adjusted P = 0.005), general memory (r = 0.15, false discovery rate P = 0.02), and processing speed (r = 0.17, false discovery rate P = 0.01) scores. These positive associations remained significant in for the d-transposition of the great arteries and Tetralogy of Fallot cohorts only in multivariable linear regression (estimated change ß = 0.7, false discovery rate P = 0.004; ß = 4.1, false discovery rate P = 0.03; and ß = 5.4, false discovery rate P = 0.003, respectively). Duration of deep hypothermic circulatory arrest was also associated with outcomes in the multivariate model and regression tree analysis. This suggests that sulcal pattern may provide an early biomarker for prediction of later neurocognitive challenges among people with congenital heart disease.


Subject(s)
Heart Defects, Congenital , Child , Female , Humans , Male , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/pathology , Cerebral Cortex/growth & development , Executive Function/physiology , Heart Defects, Congenital/complications , Heart Defects, Congenital/pathology , Magnetic Resonance Imaging , Neurodevelopmental Disorders/etiology , Neurodevelopmental Disorders/pathology , Adolescent , Young Adult
2.
Adv Exp Med Biol ; 1441: 77-85, 2024.
Article in English | MEDLINE | ID: mdl-38884705

ABSTRACT

The major events of cardiac development, including early heart formation, chamber morphogenesis and septation, and conduction system and coronary artery development, are briefly reviewed together with a short introduction to the animal species commonly used to study heart development and model congenital heart defects (CHDs).


Subject(s)
Disease Models, Animal , Heart Defects, Congenital , Heart , Animals , Heart Defects, Congenital/physiopathology , Heart Defects, Congenital/pathology , Heart/embryology , Heart/physiopathology , Heart/growth & development , Humans , Mice , Morphogenesis
3.
Adv Exp Med Biol ; 1441: 167-183, 2024.
Article in English | MEDLINE | ID: mdl-38884711

ABSTRACT

Formation of the vertebrate heart with its complex arterial and venous connections is critically dependent on patterning of the left-right axis during early embryonic development. Abnormalities in left-right patterning can lead to a variety of complex life-threatening congenital heart defects. A highly conserved pathway responsible for left-right axis specification has been uncovered. This pathway involves initial asymmetric activation of a nodal signaling cascade at the embryonic node, followed by its propagation to the left lateral plate mesoderm and activation of left-sided expression of the Pitx2 transcription factor specifying visceral organ asymmetry. Intriguingly, recent work suggests that cardiac laterality is encoded by intrinsic cell and tissue chirality independent of Nodal signaling. Thus, Nodal signaling may be superimposed on this intrinsic chirality, providing additional instructive cues to pattern cardiac situs. The impact of intrinsic chirality and the perturbation of left-right patterning on myofiber organization and cardiac function warrants further investigation. We summarize recent insights gained from studies in animal models and also some human clinical studies in a brief overview of the complex processes regulating cardiac asymmetry and their impact on cardiac function and the pathogenesis of congenital heart defects.


Subject(s)
Body Patterning , Heart Defects, Congenital , Heart , Humans , Animals , Heart/embryology , Heart/physiology , Body Patterning/genetics , Heart Defects, Congenital/genetics , Heart Defects, Congenital/physiopathology , Heart Defects, Congenital/metabolism , Heart Defects, Congenital/pathology , Signal Transduction , Gene Expression Regulation, Developmental , Nodal Protein/metabolism , Nodal Protein/genetics
4.
Adv Exp Med Biol ; 1441: 239-252, 2024.
Article in English | MEDLINE | ID: mdl-38884715

ABSTRACT

Congenital heart disease (CHD) is a leading cause of birth defect-related death. Despite significant advances, the mechanisms underlying the development of CHD are complex and remain elusive due to a lack of efficient, reproducible, and translational model systems. Investigations relied on animal models have inherent limitations due to interspecies differences. Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for disease modeling. iPSCs allow for the production of a limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine. Over the past decade, researchers have developed protocols to differentiate iPSCs to multiple cardiovascular lineages, as well as to enhance the maturity and functionality of these cells. With the development of physiologic three-dimensional cardiac organoids, iPSCs represent a powerful platform to mechanistically dissect CHD and serve as a foundation for future translational research.


Subject(s)
Cell Differentiation , Heart Defects, Congenital , Induced Pluripotent Stem Cells , Organoids , Humans , Induced Pluripotent Stem Cells/cytology , Heart Defects, Congenital/pathology , Heart Defects, Congenital/therapy , Organoids/cytology , Organoids/metabolism , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , Animals
5.
Adv Exp Med Biol ; 1441: 271-294, 2024.
Article in English | MEDLINE | ID: mdl-38884717

ABSTRACT

Cardiovascular diseases, both congenital and acquired, are the leading cause of death worldwide, associated with significant health consequences and economic burden. Due to major advances in surgical procedures, most patients with congenital heart disease (CHD) survive into adulthood but suffer from previously unrecognized long-term consequences, such as early-onset heart failure. Therefore, understanding the molecular mechanisms resulting in heart defects and the lifelong complications due to hemodynamic overload are of utmost importance. Congenital heart disease arises in the first trimester of pregnancy, due to defects in the complex morphogenetic patterning of the heart. This process is coordinated through a complicated web of intercellular communication between the epicardium, the endocardium, and the myocardium. In the postnatal heart, similar crosstalk between cardiomyocytes, endothelial cells, and fibroblasts exists during pathological hemodynamic overload that emerges as a consequence of a congenital heart defect. Ultimately, communication between cells triggers the activation of intracellular signaling circuits, which allow fine coordination of cardiac development and function. Here, we review the inter- and intracellular signaling mechanisms in the heart as they were discovered mainly in genetically modified mice.


Subject(s)
Cell Communication , Heart Defects, Congenital , Signal Transduction , Humans , Animals , Heart Defects, Congenital/genetics , Heart Defects, Congenital/metabolism , Heart Defects, Congenital/pathology , Heart Defects, Congenital/physiopathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Myocardium/metabolism , Myocardium/pathology , Mice , Pregnancy , Heart/embryology , Heart/growth & development
6.
Adv Exp Med Biol ; 1441: 777-796, 2024.
Article in English | MEDLINE | ID: mdl-38884748

ABSTRACT

The great arteries of the vertebrate carry blood from the heart to the systemic circulation and are derived from the pharyngeal arch arteries. In higher vertebrates, the pharyngeal arch arteries are a symmetrical series of blood vessels that rapidly remodel during development to become the asymmetric aortic arch arteries carrying oxygenated blood from the left ventricle via the outflow tract. At the base of the aorta, as well as the pulmonary trunk, are the semilunar valves. These valves each have three leaflets and prevent the backflow of blood into the heart. During development, the process of aortic arch and valve formation may go wrong, resulting in cardiovascular defects, and these may, at least in part, be caused by genetic mutations. In this chapter, we will review models harboring genetic mutations that result in cardiovascular defects affecting the great arteries and the semilunar valves.


Subject(s)
Aorta, Thoracic , Animals , Aorta, Thoracic/abnormalities , Humans , Mutation , Disease Models, Animal , Aortic Valve/abnormalities , Aortic Valve/pathology , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology
7.
Adv Exp Med Biol ; 1441: 761-775, 2024.
Article in English | MEDLINE | ID: mdl-38884747

ABSTRACT

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.


Subject(s)
Aorta, Thoracic , Aortic Valve , Humans , Aorta, Thoracic/abnormalities , Aorta, Thoracic/pathology , Aortic Valve/abnormalities , Aortic Valve/pathology , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Bicuspid Aortic Valve Disease/genetics , Pulmonary Valve Stenosis/genetics , Mutation , Receptor, Notch1/genetics , Aortic Valve Disease/genetics , Heart Valve Diseases/genetics , Heart Valve Diseases/pathology , Calcinosis/genetics , Calcinosis/pathology , Hematologic Diseases/genetics , Hematologic Diseases/pathology , Vestibular Diseases/genetics , Vestibular Diseases/pathology
8.
Pediatr Transplant ; 28(4): e14742, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38702926

ABSTRACT

BACKGROUND: As more pediatric patients become candidates for heart transplantation (HT), understanding pathological predictors of outcome and the accuracy of the pretransplantation evaluation are important to optimize utilization of scarce donor organs and improve outcomes. The authors aimed to investigate explanted heart specimens to identify pathologic predictors that may affect cardiac allograft survival after HT. METHODS: Explanted pediatric hearts obtained over an 11-year period were analyzed to understand the patient demographics, indications for transplant, and the clinical-pathological factors. RESULTS: In this study, 149 explanted hearts, 46% congenital heart defects (CHD), were studied. CHD patients were younger and mean pulmonary artery pressure and resistance were significantly lower than in cardiomyopathy patients. Twenty-one died or underwent retransplantation (14.1%). Survival was significantly higher in the cardiomyopathy group at all follow-up intervals. There were more deaths and the 1-, 5- and 7-year survival was lower in patients ≤10 years of age at HT. Early rejection was significantly higher in CHD patients exposed to homograft tissue, but not late rejection. Mortality/retransplantation rate was significantly higher and allograft survival lower in CHD hearts with excessive fibrosis of one or both ventricles. Anatomic diagnosis at pathologic examination differed from the clinical diagnosis in eight cases. CONCLUSIONS: Survival was better for the cardiomyopathy group and patients >10 years at HT. Prior homograft use was associated with a higher prevalence of early rejection. Ventricular fibrosis (of explant) was a strong predictor of outcome in the CHD group. We presented several pathologic findings in explanted pediatric hearts.


Subject(s)
Graft Rejection , Graft Survival , Heart Defects, Congenital , Heart Transplantation , Humans , Child , Male , Female , Child, Preschool , Infant , Adolescent , Heart Defects, Congenital/surgery , Heart Defects, Congenital/pathology , Graft Rejection/pathology , Graft Rejection/epidemiology , Retrospective Studies , Treatment Outcome , Follow-Up Studies , Cardiomyopathies/surgery , Cardiomyopathies/pathology , Reoperation , Infant, Newborn , Survival Analysis
9.
Nat Commun ; 15(1): 4166, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38755146

ABSTRACT

Failure of proper ventricular trabeculation is often associated with congenital heart disease. Support from endocardial cells, including the secretion of extracellular matrix and growth factors is critical for trabeculation. However, it is poorly understood how the secretion of extracellular matrix and growth factors is initiated and regulated by endocardial cells. We find that genetic knockout of histone deacetylase 3 in the endocardium in mice results in early embryo lethality and ventricular hypotrabeculation. Single cell RNA sequencing identifies significant downregulation of extracellular matrix components in histone deacetylase 3 knockout endocardial cells. Secretome from cultured histone deacetylase 3 knockout mouse cardiac endothelial cells lacks transforming growth factor ß3 and shows significantly reduced capacity in stimulating cultured cardiomyocyte proliferation, which is remarkably rescued by transforming growth factor ß3 supplementation. Mechanistically, we identify that histone deacetylase 3 knockout induces transforming growth factor ß3 expression through repressing microRNA-129-5p. Our findings provide insights into the pathogenesis of congenital heart disease and conceptual strategies to promote myocardial regeneration.


Subject(s)
Endocardium , Histone Deacetylases , Mice, Knockout , MicroRNAs , Myocytes, Cardiac , Animals , Endocardium/metabolism , Mice , MicroRNAs/metabolism , MicroRNAs/genetics , Histone Deacetylases/metabolism , Histone Deacetylases/genetics , Myocytes, Cardiac/metabolism , Transforming Growth Factor beta3/metabolism , Transforming Growth Factor beta3/genetics , Cell Proliferation , Myocardium/metabolism , Endothelial Cells/metabolism , Heart Defects, Congenital/genetics , Heart Defects, Congenital/metabolism , Heart Defects, Congenital/pathology , Extracellular Matrix/metabolism , Female
10.
Int J Mol Sci ; 25(10)2024 May 16.
Article in English | MEDLINE | ID: mdl-38791454

ABSTRACT

Previous omics research in patients with complex congenital heart disease and single-ventricle circulation (irrespective of the stage of palliative repair) revealed alterations in cardiac and systemic metabolism, inter alia abnormalities in energy metabolism, and inflammation, oxidative stress or endothelial dysfunction. We employed an affinity-proteomics approach focused on cell surface markers, cytokines, and chemokines in the serum of 20 adult Fontan patients with a good functioning systemic left ventricle, and we 20 matched controls to reveal any specific processes on a cellular level. Analysis of 349 proteins revealed 4 altered protein levels related to chronic inflammation, with elevated levels of syndecan-1 and glycophorin-A, as well as decreased levels of leukemia inhibitory factor and nerve growth factor-ß in Fontan patients compared to controls. All in all, this means that Fontan circulation carries specific physiological and metabolic instabilities, including chronic inflammation, oxidative stress imbalance, and consequently, possible damage to cell structure and alterations in translational pathways. A combination of proteomics-based biomarkers and the traditional biomarkers (uric acid, γGT, and cholesterol) performed best in classification (patient vs. control). A metabolism- and signaling-based approach may be helpful for a better understanding of Fontan (patho-)physiology. Syndecan-1, glycophorin-A, leukemia inhibitory factor, and nerve growth factor-ß, especially in combination with uric acid, γGT, and cholesterol, might be interesting candidate parameters to complement traditional diagnostic imaging tools and the determination of traditional biomarkers, yielding a better understanding of the development of comorbidities in Fontan patients, and they may play a future role in the identification of targets to mitigate inflammation and comorbidities in Fontan patients.


Subject(s)
Biomarkers , Blood Proteins , Fontan Procedure , Inflammation , Proteomics , Humans , Adult , Male , Inflammation/metabolism , Female , Blood Proteins/metabolism , Fontan Procedure/adverse effects , Biomarkers/blood , Proteomics/methods , Heart Defects, Congenital/surgery , Heart Defects, Congenital/metabolism , Heart Defects, Congenital/blood , Heart Defects, Congenital/pathology , Fibrosis , Young Adult , Neovascularization, Pathologic/metabolism , Oxidative Stress , Angiogenesis
11.
Matrix Biol ; 131: 1-16, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38750698

ABSTRACT

Extracellular matrix remodeling mechanisms are understudied in cardiac development and congenital heart defects. We show that matrix-degrading metalloproteases ADAMTS1 and ADAMTS5, are extensively co-expressed during mouse cardiac development. The mouse mutants of each gene have mild cardiac anomalies, however, their combined genetic inactivation to elicit cooperative roles is precluded by tight gene linkage. Therefore, we coupled Adamts1 inactivation with pharmacologic ADAMTS5 blockade to uncover stage-specific cooperative roles and investigated their potential substrates in mouse cardiac development. ADAMTS5 blockade was achieved in Adamts1 null mouse embryos using an activity-blocking monoclonal antibody during distinct developmental windows spanning myocardial compaction or cardiac septation and outflow tract rotation. Synchrotron imaging, RNA in situ hybridization, immunofluorescence microscopy and electron microscopy were used to determine the impact on cardiac development and compared to Gpc6 and ADAMTS-cleavage resistant versican mutants. Mass spectrometry-based N-terminomics was used to seek relevant substrates. Combined inactivation of ADAMTS1 and ADAMTS5 prior to 12.5 days of gestation led to dramatic accumulation of versican-rich cardiac jelly and inhibited formation of compact and trabecular myocardium, which was also observed in mice with ADAMTS cleavage-resistant versican. Combined inactivation after 12.5 days impaired outflow tract development and ventricular septal closure, generating a tetralogy of Fallot-like defect. N-terminomics of combined ADAMTS knockout and control hearts identified a cleaved glypican-6 peptide only in the controls. ADAMTS1 and ADAMTS5 expression in cells was associated with specific glypican-6 cleavages. Paradoxically, combined ADAMTS1 and ADAMTS5 inactivation reduced cardiac glypican-6 and outflow tract Gpc6 transcription. Notably, Gpc6-/- hearts demonstrated similar rotational defects as combined ADAMTS inactivated hearts and both had reduced hedgehog signaling. Thus, versican proteolysis in cardiac jelly at the canonical Glu441-Ala442 site is cooperatively mediated by ADAMTS1 and ADAMTS5 and required for proper ventricular cardiomyogenesis, whereas, reduced glypican-6 after combined ADAMTS inactivation impairs hedgehog signaling, leading to outflow tract malrotation.


Subject(s)
ADAMTS1 Protein , ADAMTS5 Protein , Glypicans , Heart , Proteolysis , Versicans , Animals , Mice , Versicans/metabolism , Versicans/genetics , ADAMTS5 Protein/metabolism , ADAMTS5 Protein/genetics , ADAMTS1 Protein/metabolism , ADAMTS1 Protein/genetics , Glypicans/metabolism , Glypicans/genetics , Heart/growth & development , Mice, Knockout , Gene Expression Regulation, Developmental , Heart Defects, Congenital/genetics , Heart Defects, Congenital/metabolism , Heart Defects, Congenital/pathology
12.
Genes (Basel) ; 15(5)2024 05 17.
Article in English | MEDLINE | ID: mdl-38790267

ABSTRACT

Brugada syndrome is a rare arrhythmogenic syndrome associated mainly with pathogenic variants in the SCN5A gene. Right ventricle outflow tract fibrosis has been reported in some cases of patients diagnosed with Brugada syndrome. Pulmonary atresia with an intact ventricular septum is characterized by the lack of a functional pulmonary valve, due to the underdevelopment of the right ventricle outflow tract. We report, for the first time, a 4-year-old boy with pulmonary atresia with an intact ventricular septum who harbored a pathogenic de novo variant in SCN5A, and the ajmaline test unmasked a type-1 Brugada pattern. We suggest that deleterious variants in the SCN5A gene could be implicated in pulmonary atresia with an intact ventricular septum embryogenesis, leading to overlapping phenotypes.


Subject(s)
Brugada Syndrome , NAV1.5 Voltage-Gated Sodium Channel , Pulmonary Atresia , Humans , Pulmonary Atresia/genetics , Pulmonary Atresia/pathology , Male , Brugada Syndrome/genetics , Brugada Syndrome/pathology , Child, Preschool , NAV1.5 Voltage-Gated Sodium Channel/genetics , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Ventricular Septum/pathology
13.
Exp Mol Pathol ; 137: 104907, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38820762

ABSTRACT

Congenital Heart Diseases (CHDs) are a group of structural abnormalities or defects of the heart that are present at birth. CHDs could be connected to sudden death (SD), defined by the WHO (World Health Organization) as "death occurring within 24 h after the onset of the symptoms" in an apparently "healthy" subject. These conditions can range from relatively mild defects to severe, life-threatening anomalies. The prevalence of CHDs varies across populations, but they affect millions of individuals worldwide. This article aims to discuss the post-mortem investigation of death related to CHDs, exploring the forensic approach, current methodologies, challenges, and potential advancements in this challenging field. A further goal of this article is to provide a guide for understanding these complex diseases, highlighting the pivotal role of autopsy, histopathology, and genetic investigations in defining the cause of death, and providing evidence about the translational use of autopsy reports. Forensic investigations play a crucial role in understanding the complexities of CHDs and determining the cause of death accurately. Through collaboration between medical professionals and forensic experts, meticulous examinations, and analysis of evidence, valuable insights can be gained. These insights not only provide closure to the families affected but also contribute to the prevention of future tragedies.


Subject(s)
Autopsy , Cause of Death , Heart Defects, Congenital , Humans , Heart Defects, Congenital/pathology , Heart Defects, Congenital/mortality , Heart Defects, Congenital/genetics , Forensic Medicine/methods
14.
Circ Res ; 134(10): e112-e132, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38618720

ABSTRACT

BACKGROUND: The resiliency of embryonic development to genetic and environmental perturbations has been long appreciated; however, little is known about the mechanisms underlying the robustness of developmental processes. Aberrations resulting in neonatal lethality are exemplified by congenital heart disease arising from defective morphogenesis of pharyngeal arch arteries (PAAs) and their derivatives. METHODS: Mouse genetics, lineage tracing, confocal microscopy, and quantitative image analyses were used to investigate mechanisms of PAA formation and repair. RESULTS: The second heart field (SHF) gives rise to the PAA endothelium. Here, we show that the number of SHF-derived endothelial cells (ECs) is regulated by VEGFR2 (vascular endothelial growth factor receptor 2) and Tbx1. Remarkably, when the SHF-derived EC number is decreased, PAA development can be rescued by the compensatory endothelium. Blocking such compensatory response leads to embryonic demise. To determine the source of compensating ECs and mechanisms regulating their recruitment, we investigated 3-dimensional EC connectivity, EC fate, and gene expression. Our studies demonstrate that the expression of VEGFR2 by the SHF is required for the differentiation of SHF-derived cells into PAA ECs. The deletion of 1 VEGFR2 allele (VEGFR2SHF-HET) reduces SHF contribution to the PAA endothelium, while the deletion of both alleles (VEGFR2SHF-KO) abolishes it. The decrease in SHF-derived ECs in VEGFR2SHF-HET and VEGFR2SHF-KO embryos is complemented by the recruitment of ECs from the nearby veins. Compensatory ECs contribute to PAA derivatives, giving rise to the endothelium of the aortic arch and the ductus in VEGFR2SHF-KO mutants. Blocking the compensatory response in VEGFR2SHF-KO mutants results in embryonic lethality shortly after mid-gestation. The compensatory ECs are absent in Tbx1+/- embryos, a model for 22q11 deletion syndrome, leading to unpredictable arch artery morphogenesis and congenital heart disease. Tbx1 regulates the recruitment of the compensatory endothelium in an SHF-non-cell-autonomous manner. CONCLUSIONS: Our studies uncover a novel buffering mechanism underlying the resiliency of PAA development and remodeling.


Subject(s)
Aorta, Thoracic , Endothelial Cells , Heart Defects, Congenital , T-Box Domain Proteins , Vascular Endothelial Growth Factor Receptor-2 , Animals , Vascular Endothelial Growth Factor Receptor-2/metabolism , Vascular Endothelial Growth Factor Receptor-2/genetics , Mice , Aorta, Thoracic/embryology , Aorta, Thoracic/metabolism , Heart Defects, Congenital/genetics , Heart Defects, Congenital/metabolism , Heart Defects, Congenital/pathology , Heart Defects, Congenital/embryology , T-Box Domain Proteins/metabolism , T-Box Domain Proteins/genetics , Endothelial Cells/metabolism , Gene Expression Regulation, Developmental , Cell Differentiation , Mice, Inbred C57BL
15.
Eur J Med Genet ; 69: 104942, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38677542

ABSTRACT

Telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly (TEBC) syndrome is a rare autosomal dominant condition, recently linked to the protein kinase D1 (PRKD1) gene. The phenotype of TEBC remains incomplete at this point. Our aim is to improve the characterization of the clinical and molecular aspects of the TEBC syndrome. We report on the 8th patient carrying a heterozygous de novo variation of PRKD1 c.2134G > A, p. (Val712Met) identified by trio exome sequencing. The proband presents with partial atrioventricular septal defect, brachydactyly, ectodermal dysplasia, telangiectasia that developed in childhood, intellectual disability with microcephaly, multicystic renal dysplasia and moderate hormonal resistance. In view of this 8th description and review of the literature, it appears that neurodevelopmental disorders and microcephaly are frequently associated with PRKD1 missense variants, adding to the four main clinical signs described initially in the TEBC syndrome. Further descriptions are required to confirm the observed endocrine and kidney abnormalities. This should contribute to a more comprehensive understanding of the phenotypic spectrum and may help establish genotype-phenotype correlations. In the context of genotype-first strategy, accurate patient descriptions are fundamental. Characterization of specific syndromic associations is essential for variant interpretation support and patient follow-up, even in very rare diseases, such as the TEBC syndrome.


Subject(s)
Ectodermal Dysplasia , Heart Defects, Congenital , Humans , Ectodermal Dysplasia/genetics , Ectodermal Dysplasia/pathology , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Phenotype , Brachydactyly/genetics , Brachydactyly/pathology , Male , Telangiectasis/genetics , Telangiectasis/pathology , Female , Mutation, Missense , Syndrome , Microcephaly/genetics , Microcephaly/pathology , Child , Protein Kinase C
16.
Dis Model Mech ; 17(6)2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38501224

ABSTRACT

De novo truncating variants in fibrosin-like 1 (FBRSL1), a member of the AUTS2 gene family, cause a disability syndrome, including organ malformations such as heart defects. Here, we use Xenopus laevis to investigate whether Fbrsl1 plays a role in heart development. Xenopus laevis fbrsl1 is expressed in tissues relevant for heart development, and morpholino-mediated knockdown of Fbrsl1 results in severely hypoplastic hearts. Our data suggest that Fbrsl1 is required for the development of the first heart field, which contributes to the ventricle and the atria, but not for the second heart field, which gives rise to the outflow tract. The morphant heart phenotype could be rescued using a human N-terminal FBRSL1 isoform that contains an alternative exon, but lacks the AUTS2 domain. N-terminal isoforms carrying patient variants failed to rescue. Interestingly, a long human FBRSL1 isoform, harboring the AUTS2 domain, also did not rescue the morphant heart defects. Thus, our data suggest that different FBRSL1 isoforms may have distinct functions and that only the short N-terminal isoform, appears to be critical for heart development.


Subject(s)
Heart Defects, Congenital , Heart , Protein Isoforms , Xenopus Proteins , Xenopus laevis , Animals , Xenopus laevis/embryology , Humans , Xenopus Proteins/metabolism , Xenopus Proteins/genetics , Heart/embryology , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Protein Isoforms/metabolism , Protein Isoforms/genetics , Phenotype , Gene Knockdown Techniques , Gene Expression Regulation, Developmental
17.
Cardiovasc Pathol ; 71: 107636, 2024.
Article in English | MEDLINE | ID: mdl-38521140

ABSTRACT

Quadricuspid pulmonic valve is a rare congenital abnormality and because of its difficult non-invasive assessment, it is usually discovered incidentally at autopsies (reported prevalence in post-mortem specimens ranges from 1 in 400 to 1 in 2000). Unlike a bicuspid pulmonary valve, it rarely presents with clinical complications, such as valvular insufficiency or stenosis. Abnormal function is rarely reported in cases that are not associated with other congenital heart disease. With increased sophistication of imaging coincidental quadricuspid valves autopsy studies are important to understand the anatomical consequences of this finding. Our case series identified 21 QPV cases from the Victorian Institute of Forensic Medicine, Melbourne and St George's University of London, Department of Cardiovascular Pathology. Cases were identified through local database searches and review of autopsy/cardiac examination reports over a 20-year period. Available photographs were also systematically examined. Fifteen cases had causes of death with no direct causality to cardiac valvular pathology alone. Six cases were considered unascertained or similar (sudden arrhythmic death syndrome and sudden unexpected death in epilepsy). The presence of QPV in these instances were uncertain but thought to be unlikely contributory to death, due to the absence of pulmonary valvular complications.


Subject(s)
Autopsy , Pulmonary Valve , Humans , Pulmonary Valve/abnormalities , Pulmonary Valve/pathology , Pulmonary Valve/diagnostic imaging , Male , Female , Middle Aged , Adult , Aged , Young Adult , Cause of Death , Incidence , Adolescent , Heart Defects, Congenital/pathology , Heart Defects, Congenital/epidemiology , Heart Defects, Congenital/diagnostic imaging , Incidental Findings , Aged, 80 and over , Child
19.
J Hum Genet ; 69(5): 215-222, 2024 May.
Article in English | MEDLINE | ID: mdl-38409496

ABSTRACT

Although the molecular mechanisms underlying congenital heart disease (CHD) remain poorly understood, recent advances in genetic analysis have facilitated the exploration of causative genes for CHD. We reported that the pathogenic variant c.1617del of TMEM260, which encodes a transmembrane protein, is highly associated with CHD, specifically persistent truncus arteriosus (PTA), the most severe cardiac outflow tract (OFT) defect. Using whole-exome sequencing, the c.1617del variant was identified in two siblings with PTA in a Japanese family and in three of the 26 DNAs obtained from Japanese individuals with PTA. The c.1617del of TMEM260 has been found only in East Asians, especially Japanese and Korean populations, and the frequency of this variant in PTA is estimated to be next to that of the 22q11.2 deletion, the most well-known genetic cause of PTA. Phenotype of patients with c.1617del appears to be predominantly in the heart, although TMEM260 is responsible for structural heart defects and renal anomalies syndrome (SHDRA). The mouse TMEM260 variant (p.W535Cfs*56), synonymous with the human variant (p.W539Cfs*9), exhibited truncation and downregulation by western blotting, and aggregation by immunocytochemistry. In situ hybridization demonstrated that Tmem260 is expressed ubiquitously during embryogenesis, including in the development of cardiac OFT implicated in PTA. This expression may be regulated by a ~ 0.8 kb genomic region in intron 3 of Tmem260 that includes multiple highly conserved binding sites for essential cardiac transcription factors, thus revealing that the c.1617del variant of TMEM260 is the major single-gene variant responsible for PTA in the Japanese population.


Subject(s)
Heart Defects, Congenital , Membrane Proteins , Animals , Female , Humans , Male , Mice , Asian People/genetics , East Asian People , Exome Sequencing , Genetic Predisposition to Disease , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Japan , Membrane Proteins/genetics , Pedigree , Phenotype
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