Mitochondrial MICOS complex genes, implicated in hypoplastic left heart syndrome, maintain cardiac contractility and actomyosin integrity.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with a likely oligogenic etiology, but our understanding of the genetic complexities and pathogenic mechanisms leading to HLHS is limited. We performed whole genome sequencing (WGS) on 183 HLHS patient-parent trios to identify candidate genes, which were functionally tested in the heart model. Bioinformatic analysis of WGS data from an index family of a HLHS proband born to consanguineous parents prioritized 9 candidate genes with rare, predicted damaging homozygous variants.

Isolated Absent Aortic Valves: A Unique Fetal Case With Echocardiographic, Pathologic, and Genetic Correlation.

We present a 22-week fetus with isolated absent aortic valve and inverse circular shunt. The pregnancy was interrupted. Here, echocardiography and pathology images demonstrate this rare entity.

ETS1 loss in mice impairs cardiac outflow tract septation via a cell migration defect autonomous to the neural crest.

Ets1 deletion in some mouse strains causes septal defects and has been implicated in human congenital heart defects in Jacobsen syndrome, in which one copy of the Ets1 gene is missing. Here, we demonstrate that loss of Ets1 in mice results in a decrease in neural crest (NC) cells migrating into the proximal outflow tract cushions during early heart development, with subsequent malalignment of the cushions relative to the muscular ventricular septum, resembling double outlet right ventricle (DORV) defects in humans. Consistent with this, we find that cultured cardiac NC cells from Ets1 mutant mice or derived from iPS cells from Jacobsen patients exhibit decreased migration speed and impaired cell-to-cell interactions.

Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction.

Rationale: Jacobsen syndrome is a rare chromosomal disorder caused by deletions in the long arm of human chromosome 11, resulting in multiple developmental defects including congenital heart defects. Combined studies in humans and genetically engineered mice implicate that loss of ETS1 (E26 transformation specific 1) is the cause of congenital heart defects in Jacobsen syndrome, but the underlying molecular and cellular mechanisms are unknown.

Objective: To determine the role of ETS1 in heart development, specifically its roles in coronary endothelium and endocardium and the mechanisms by which loss of ETS1 causes coronary vascular defects and ventricular noncompaction.

ETS1 and HLHS: Implications for the Role of the Endocardium.

We have identified the ETS1 gene as the cause of congenital heart defects, including an unprecedented high frequency of HLHS, in the chromosomal disorder Jacobsen syndrome. Studies in demonstrated a critical role for ETS1 in heart cell fate determination and cell migration, suggesting that the impairment of one or both processes can underlie the pathogenesis of HLHS. Our studies determined that ETS1 is expressed in the cardiac neural crest and endocardium in the developing murine heart, implicating one or both lineages in the development of HLHS.

High Level of Serum Uric Acid induced Monocyte Inflammation is Related to Coronary Calcium Deposition in the Middle-Aged and Elder Population of China: A five-year Prospective Cohort Study.

Background: Serum uric acid (SUA) is suspected to be associated with atherosclerosis and calcium deposition in atherosclerosis is known to related poor prognosis, yet there is no cohort study on the aged in China. We aimed to investigate the relationships between SUA levels and coronary calcium deposition in the middle-aged and elderly populations in China.

Methods: A total of 326 participants between the ages of 50 and 85 who had undergone a coronary CT scan in 2015 at the Huadong Hospital Affiliated to Fudan University (Shanghai, China) were included in this study.

Combined Non-Invasive Cardiac Imaging and Genetic Testing of Elite Volleyball Players: A Ten-Year Experience.

Sudden cardiac death in athletes is a devastating event. Although significant progress has been made in identifying the underlying pathophysiology and genetic basis for sudden cardiac death in young athletes, controversy exists regarding cost-effective screening measures to identify at-risk individuals. In this report we describe our ten-year experience performing cardiovascular assessments on 150 members of the United States Men's and Women's National Volleyball teams.

The Needle in the Haystack-Searching for Genetic and Epigenetic Differences in Monozygotic Twins Discordant for Tetralogy of Fallot.

Congenital heart defects (CHDs) are the most common birth defect in human with an incidence of almost 1% of all live births. Most cases have a multifactorial origin with both genetics and the environment playing a role in its development and progression. Adding an epigenetic component to this aspect is exemplified by monozygotic twins which share the same genetic background but have a different disease status.

Patient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome.

Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multidisciplinary platform was established to functionally evaluate novel CHD gene candidates, based on whole-genome and iPSC RNA sequencing of a HLHS family-trio. Filtering for rare variants and altered expression in proband iPSCs prioritized 10 candidates.

Intrinsic Endocardial Defects Contribute to Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease characterized by abnormalities in the left ventricle, associated valves, and ascending aorta. Studies have shown intrinsic myocardial defects but do not sufficiently explain developmental defects in the endocardial-derived cardiac valve, septum, and vasculature. Here, we identify a developmentally impaired endocardial population in HLHS through single-cell RNA profiling of hiPSC-derived endocardium and human fetal heart tissue with an underdeveloped left ventricle.

Overexpression of in the Developing Heart Causes Valvar and Contractility Defects: Implications for Human Congenital Heart Disease.

Left-sided congenital heart defects (CHDs) are among the most common forms of congenital heart disease, but a disease-causing gene has only been identified in a minority of cases. Here, we identified a candidate gene for CHDs, , that was associated with a chromosomal balanced translocation t(2;8)(q37;p11) in a patient with left-sided heart and aortic valve defects. The breakpoint was in the 5' untranslated region of the gene at 2q37, which suggested that the break affected the levels of gene expression.

Model system identification of novel congenital heart disease gene candidates: focus on RPL13.

Genetics is a significant factor contributing to congenital heart disease (CHD), but our understanding of the genetic players and networks involved in CHD pathogenesis is limited. Here, we searched for de novo copy number variations (CNVs) in a cohort of 167 CHD patients to identify DNA segments containing potential pathogenic genes. Our search focused on new candidate disease genes within 19 deleted de novo CNVs, which did not cover known CHD genes.

Partial Jacobsen syndrome phenotype in a patient with a de novo frameshift mutation in the ETS1 transcription factor.

Jacobsen syndrome (OMIM #147791) is a rare contiguous gene disorder caused by deletions in distal 11q. The clinical phenotype is variable and can include dysmorphic features, varying degrees of intellectual disability, behavioral problems including autism and attention deficit hyperactivity disorder, congenital heart defects, structural kidney defects, genitourinary problems, immunodeficiency, and a bleeding disorder due to impaired platelet production and function. Previous studies combining both human and animal systems have implicated several disease-causing genes in distal 11q that contribute to the Jacobsen syndrome phenotype.

Successful Management of a Patient With Jacobsen Syndrome and Hypoplastic Left Heart Syndrome.

Jacobsen syndrome (JS) is a rare genetic condition characterized by intellectual disability, hematologic abnormalities, and congenital heart defects. A male infant presented at birth with phenotypic findings of JS and echocardiographic findings of hypoplastic left heart syndrome (HLHS). Array comparative genomic hybridization was performed at age three days and revealed an 8.

Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?

Hypoplastic left heart syndrome occurs in up to 3% of all infants born with congenital heart disease and is a leading cause of death in this population. Although there is strong evidence for a genetic component, a specific genetic cause is only known in a small subset of patients, consistent with a multifactorial etiology for the syndrome. There is controversy surrounding the mechanisms underlying the syndrome, which is likely due, in part, to the phenotypic variability of the disease.

Endothelial-specific deletion of Ets-1 attenuates Angiotensin II-induced cardiac fibrosis via suppression of endothelial-to-mesenchymal transition.

Cardiac fibrosis is a common feature in chronic hypertension patients with advanced heart failure, and endothelial-tomesenchymal transition (EndMT) is known to promote Angiotensin II (Ang II)-mediated cardiac fibrosis. Previous studies have suggested a potential role for the transcription factor, ETS-1, in Ang II-mediated cardiac remodeling, however the mechanism are not well defined. In this study, we found that mice with endothelial Ets-1 deletion showed reduced cardiac fibrosis and hypertrophy following Ang II infusion.

Gene-targeted deletion in mice of the Ets-1 transcription factor, a candidate gene in the Jacobsen syndrome kidney "critical region," causes abnormal kidney development.

Ets-1 is a member of the Ets family of transcription factors and has critical roles in multiple biological functions. Structural kidney defects occur at an increased frequency in Jacobsen syndrome (OMIM #147791), a rare chromosomal disorder caused by deletions in distal 11q, implicating at least one causal gene in distal 11q. In this study, we define an 8.

Arterial Switch Operation in a Patient With Ehlers-Danlos Syndrome Type IV.

Ehlers-Danlos syndrome vascular type IV is characterized by translucent skin, easy bruising, and fragility of arteries. A full-term female infant presented at four weeks of age with a diagnosis of d-transposition of the great arteries with restrictive atrial septal defect. She successfully underwent emergent balloon atrial septostomy and placement of patent ductus arteriosus (PDA) stent.

Tissue specific requirements for WNT11 in developing outflow tract and dorsal mesenchymal protrusion.

Correct cardiac development is essential for fetal and adult life. Disruptions in a variety of signaling pathways result in congenital heart defects, including outflow and inflow tract defects. We previously found that WNT11 regulates outflow tract development.

Utility of Genetic Testing in Elite Volleyball Players with Aortic Root Dilation.

Unlabelled: Basketball and volleyball attract individuals with a characteristic biophysical profile, mimicking features of Marfan syndrome. Consequently, identification of these abnormalities can be lifesaving.

Purpose: To determine how physical examination, echocardiography, and genetic screening can identify elite volleyball players with a previously undiagnosed aortopathy.

Brain hemorrhages in Jacobsen syndrome: A retrospective review of six cases and clinical recommendations.

Jacobsen syndrome is a rare chromosomal disorder caused by distal deletions in the long arm of chromosome 11. All patients with Jacobsen syndrome have Paris-Trousseau syndrome, a bleeding disorder that causes neonatal thrombocytopenia, and persistent platelet dysfunction. Despite that, to date there are no reported cases of hemorrhagic strokes occurring in patients with Jacobsen syndrome.

PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking.

Jacobsen syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour.