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

2019 ◽  
Vol 28 (23) ◽  
pp. 3954-3969 ◽  
Author(s):  
Analyne M Schroeder ◽  
Massoud Allahyari ◽  
Georg Vogler ◽  
Maria A Missinato ◽  
Tanja Nielsen ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
High Throughput ◽  
Heart Development ◽  
Congenital Heart ◽  
De Novo ◽  
Model Systems ◽  
New Genes ◽  
Cardiac Model

Abstract 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. For this study, we developed an integrated high-throughput phenotypical platform to probe for defects in cardiogenesis and cardiac output in human induced pluripotent stem cell (iPSC)-derived multipotent cardiac progenitor (MCPs) cells and, in parallel, in the Drosophila in vivo heart model. Notably, knockdown (KD) in MCPs of RPL13, a ribosomal gene and SON, an RNA splicing cofactor, reduced proliferation and differentiation of cardiomyocytes, while increasing fibroblasts. In the fly, heart-specific RpL13 KD, predominantly at embryonic stages, resulted in a striking ‘no heart’ phenotype. KD of Son and Pdss2, among others, caused structural and functional defects, including reduced or abolished contractility, respectively. In summary, using a combination of human genetics and cardiac model systems, we identified new genes as candidates for causing human CHD, with particular emphasis on ribosomal genes, such as RPL13. This powerful, novel approach of combining cardiac phenotyping in human MCPs and in the in vivo Drosophila heart at high throughput will allow for testing large numbers of CHD candidates, based on patient genomic data, and for building upon existing genetic networks involved in heart development and disease.

scholarly journals High throughput in vivo functional validation of candidate congenital heart disease genes in Drosophila

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jun-yi Zhu ◽  
Yulong Fu ◽  
Margaret Nettleton ◽  
Adam Richman ◽  
Zhe Han
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
High Throughput ◽  
Congenital Heart ◽  
De Novo ◽  
Disease Risk ◽  
In Vivo Model ◽  
Disease Genes ◽  
Specific Patient

Genomic sequencing has implicated large numbers of genes and de novo mutations as potential disease risk factors. A high throughput in vivo model system is needed to validate gene associations with pathology. We developed a Drosophila-based functional system to screen candidate disease genes identified from Congenital Heart Disease (CHD) patients. 134 genes were tested in the Drosophila heart using RNAi-based gene silencing. Quantitative analyses of multiple cardiac phenotypes demonstrated essential structural, functional, and developmental roles for more than 70 genes, including a subgroup encoding histone H3K4 modifying proteins. We also demonstrated the use of Drosophila to evaluate cardiac phenotypes resulting from specific, patient-derived alleles of candidate disease genes. We describe the first high throughput in vivo validation system to screen candidate disease genes identified from patients. This approach has the potential to facilitate development of precision medicine approaches for CHD and other diseases associated with genetic factors.

scholarly journals Molecular Genetics and Complex Inheritance of Congenital Heart Disease

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1020
Author(s):  
Nicholas S. Diab ◽  
Syndi Barish ◽  
Weilai Dong ◽  
Shujuan Zhao ◽  
Garrett Allington ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
High Throughput ◽  
Congenital Heart ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Copy Number Variations ◽  
De Novo Mutations ◽  
Genomic Technologies ◽  
Chd Risk

Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. Transmitted mutations have also been identified through sequencing of population scale CHD cohorts, and many transmitted mutations are enriched in cilia genes and Notch or VEGF pathway genes. While we have come a long way in identifying the causes of CHD, more work is required to end the diagnostic odyssey for all CHD families. Complex genetic explanations of CHD are emerging but will require increasingly sophisticated analysis strategies applied to very large CHD cohorts before they can come to fruition in providing molecular diagnoses to genetically unsolved patients. In this review, we discuss the genetic architecture of CHD and biological pathways involved in its pathogenesis.

scholarly journals Case report: adult onset diabetes with partial pancreatic agenesis and congenital heart disease due to a de novo GATA6 mutation

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Begona Sanchez-Lechuga ◽  
Muhammad Saqlain ◽  
Nicholas Ng ◽  
Kevin Colclough ◽  
Conor Woods ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Case Report ◽  
Congenital Heart ◽  
De Novo ◽  
Adult Onset ◽  
Onset Diabetes ◽  
Adult Onset Diabetes ◽  
Pancreatic Agenesis

scholarly journals Decoding Genetics of Congenital Heart Disease Using Patient-Derived Induced Pluripotent Stem Cells (iPSCs)

2021 ◽  
Vol 9 ◽  
Author(s):  
Hui Lin ◽  
Kim L. McBride ◽  
Vidu Garg ◽  
Ming-Tao Zhao
Keyword(s):  
Stem Cells ◽  
Congenital Heart Disease ◽  
Heart Disease ◽  
Induced Pluripotent Stem Cells ◽  
Genome Sequencing ◽  
Pluripotent Stem Cells ◽  
Congenital Heart ◽  
Model Systems ◽  
Patient Specific ◽  
Induced Pluripotent

Congenital heart disease (CHD) is the most common cause of infant death associated with birth defects. Recent next-generation genome sequencing has uncovered novel genetic etiologies of CHD, from inherited and de novo variants to non-coding genetic variants. The next phase of understanding the genetic contributors of CHD will be the functional illustration and validation of this genome sequencing data in cellular and animal model systems. Human induced pluripotent stem cells (iPSCs) have opened up new horizons to investigate genetic mechanisms of CHD using clinically relevant and patient-specific cardiac cells such as cardiomyocytes, endothelial/endocardial cells, cardiac fibroblasts and vascular smooth muscle cells. Using cutting-edge CRISPR/Cas9 genome editing tools, a given genetic variant can be corrected in diseased iPSCs and introduced to healthy iPSCs to define the pathogenicity of the variant and molecular basis of CHD. In this review, we discuss the recent progress in genetics of CHD deciphered by large-scale genome sequencing and explore how genome-edited patient iPSCs are poised to decode the genetic etiologies of CHD by coupling with single-cell genomics and organoid technologies.

scholarly journals Mending a broken heart: In vitro, in vivo and in silico models of congenital heart disease

2021 ◽  
Vol 14 (3) ◽  
pp. dmm047522
Author(s):  
Abdul Jalil Rufaihah ◽  
Ching Kit Chen ◽  
Choon Hwai Yap ◽  
Citra N. Z. Mattar
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Computational Models ◽  
Developing Heart ◽  
Heterogenous Group ◽  
In Silico Models ◽  
Large Animals

ABSTRACTBirth defects contribute to ∼0.3% of global infant mortality in the first month of life, and congenital heart disease (CHD) is the most common birth defect among newborns worldwide. Despite the significant impact on human health, most treatments available for this heterogenous group of disorders are palliative at best. For this reason, the complex process of cardiogenesis, governed by multiple interlinked and dose-dependent pathways, is well investigated. Tissue, animal and, more recently, computerized models of the developing heart have facilitated important discoveries that are helping us to understand the genetic, epigenetic and mechanobiological contributors to CHD aetiology. In this Review, we discuss the strengths and limitations of different models of normal and abnormal cardiogenesis, ranging from single-cell systems and 3D cardiac organoids, to small and large animals and organ-level computational models. These investigative tools have revealed a diversity of pathogenic mechanisms that contribute to CHD, including genetic pathways, epigenetic regulators and shear wall stresses, paving the way for new strategies for screening and non-surgical treatment of CHD. As we discuss in this Review, one of the most-valuable advances in recent years has been the creation of highly personalized platforms with which to study individual diseases in clinically relevant settings.

scholarly journals Validating the Paradigm That Biomechanical Forces Regulate Embryonic Cardiovascular Morphogenesis and Are Fundamental in the Etiology of Congenital Heart Disease

2020 ◽  
Vol 7 (2) ◽  
pp. 23
Author(s):  
Bradley B. Keller ◽  
William J. Kowalski ◽  
Joseph P. Tinney ◽  
Kimimasa Tobita ◽  
Norman Hu
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Chick Embryo ◽  
Congenital Heart ◽  
Imaging Techniques ◽  
Tissue Growth ◽  
Model Systems ◽  
Loading Conditions ◽  
Biomechanical Loading ◽  
Biomechanical Forces

The goal of this review is to provide a broad overview of the biomechanical maturation and regulation of vertebrate cardiovascular (CV) morphogenesis and the evidence for mechanistic relationships between function and form relevant to the origins of congenital heart disease (CHD). The embryonic heart has been investigated for over a century, initially focusing on the chick embryo due to the opportunity to isolate and investigate myocardial electromechanical maturation, the ability to directly instrument and measure normal cardiac function, intervene to alter ventricular loading conditions, and then investigate changes in functional and structural maturation to deduce mechanism. The paradigm of “Develop and validate quantitative techniques, describe normal, perturb the system, describe abnormal, then deduce mechanisms” was taught to many young investigators by Dr. Edward B. Clark and then validated by a rapidly expanding number of teams dedicated to investigate CV morphogenesis, structure–function relationships, and pathogenic mechanisms of CHD. Pioneering studies using the chick embryo model rapidly expanded into a broad range of model systems, particularly the mouse and zebrafish, to investigate the interdependent genetic and biomechanical regulation of CV morphogenesis. Several central morphogenic themes have emerged. First, CV morphogenesis is inherently dependent upon the biomechanical forces that influence cell and tissue growth and remodeling. Second, embryonic CV systems dynamically adapt to changes in biomechanical loading conditions similar to mature systems. Third, biomechanical loading conditions dynamically impact and are regulated by genetic morphogenic systems. Fourth, advanced imaging techniques coupled with computational modeling provide novel insights to validate regulatory mechanisms. Finally, insights regarding the genetic and biomechanical regulation of CV morphogenesis and adaptation are relevant to current regenerative strategies for patients with CHD.

scholarly journals Navigating the non-coding genome in heart development and Congenital Heart Disease

2019 ◽  
Vol 107 ◽  
pp. 11-23 ◽  
Author(s):  
Gulrez Chahal ◽  
Sonika Tyagi ◽  
Mirana Ramialison
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Heart Development ◽  
Congenital Heart
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