scholarly journals Focused Strategies for Defining the Genetic Architecture of Congenital Heart Defects

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 827
Author(s):  
Lisa J. Martin ◽  
D Woodrow Benson
Keyword(s):  
Genetic Variation ◽  
Congenital Heart Defects ◽  
Heart Development ◽  
Genetic Architecture ◽  
Congenital Heart ◽  
Rare Variants ◽  
Heart Defects ◽  
Genetic Origin ◽  
Genetic Studies ◽  
The Ideal

Congenital heart defects (CHD) are malformations present at birth that occur during heart development. Increasing evidence supports a genetic origin of CHD, but in the process important challenges have been identified. This review begins with information about CHD and the importance of detailed phenotyping of study subjects. To facilitate appropriate genetic study design, we review DNA structure, genetic variation in the human genome and tools to identify the genetic variation of interest. Analytic approaches powered for both common and rare variants are assessed. While the ideal outcome of genetic studies is to identify variants that have a causal role, a more realistic goal for genetic analytics is to identify variants in specific genes that influence the occurrence of a phenotype and which provide keys to open biologic doors that inform how the genetic variants modulate heart development. It has never been truer that good genetic studies start with good planning. Continued progress in unraveling the genetic underpinnings of CHD will require multidisciplinary collaboration between geneticists, quantitative scientists, clinicians, and developmental biologists.

Genetic variation in the COL6A1 region is associated with congenital heart defects in trisomy 21 (Down's syndrome)

1995 ◽  
Vol 59 (3) ◽  
pp. 253-269 ◽  
Author(s):  
G. E. DAVIES ◽  
C. M. HOWARD ◽  
M. J. FARRER ◽  
M. M. COLEMAN ◽  
L. B. BENNETT ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Congenital Heart Defects ◽  
Trisomy 21 ◽  
Congenital Heart ◽  
Heart Defects ◽  
Down's Syndrome ◽  
Down’S Syndrome

scholarly journals Say NO to ROS: Their Roles in Embryonic Heart Development and Pathogenesis of Congenital Heart Defects in Maternal Diabetes

Antioxidants ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 436 ◽  
Author(s):  
Engineer ◽  
Saiyin ◽  
Greco ◽  
Feng
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Heart Defects ◽  
Maternal Diabetes ◽  
Embryonic Heart ◽  
Pregestational Diabetes ◽  
Enos Uncoupling

Congenital heart defects (CHDs) are the most prevalent and serious birth defect, occurring in 1% of all live births. Pregestational maternal diabetes is a known risk factor for the development of CHDs, elevating the risk in the child by more than four-fold. As the prevalence of diabetes rapidly rises among women of childbearing age, there is a need to investigate the mechanisms and potential preventative strategies for these defects. In experimental animal models of pregestational diabetes induced-CHDs, upwards of 50% of offspring display congenital malformations of the heart, including septal, valvular, and outflow tract defects. Specifically, the imbalance of nitric oxide (NO) and reactive oxygen species (ROS) signaling is a major driver of the development of CHDs in offspring of mice with pregestational diabetes. NO from endothelial nitric oxide synthase (eNOS) is crucial to cardiogenesis, regulating various cellular and molecular processes. In fact, deficiency in eNOS results in CHDs and coronary artery malformation. Embryonic hearts from diabetic dams exhibit eNOS uncoupling and oxidative stress. Maternal treatment with sapropterin, a cofactor of eNOS, and antioxidants such as N-acetylcysteine, vitamin E, and glutathione as well as maternal exercise have been shown to improve eNOS function, reduce oxidative stress, and lower the incidence CHDs in the offspring of mice with pregestational diabetes. This review summarizes recent data on pregestational diabetes-induced CHDs, and offers insights into the important roles of NO and ROS in embryonic heart development and pathogenesis of CHDs in maternal diabetes.

scholarly journals Semaphorin3f as an intrinsic regulator of chamber-specific heart development

2021 ◽  
Author(s):  
Rami Halabi ◽  
Paula B. Cechmanek ◽  
Carrie L. Hehr ◽  
Sarah McFarlane
Keyword(s):  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Molecular Mechanisms ◽  
Heart Defects ◽  
Border Region ◽  
Specific Gene ◽  
Atrioventricular Canal ◽  
Term Survival ◽  
Ventricular Cardiomyocytes

During development a pool of precursors form a heart with atrial and ventricular chambers that exhibit distinct transcriptional and electrophysiological properties. Normal development of these chambers is essential for full term survival of the fetus, and deviations result in congenital heart defects. The large number of genes that may cause congenital heart defects when mutated, and the genetic variability and penetrance of the ensuing phenotypes, reveals a need to understand the molecular mechanisms that allow for the formation of chamber-specific cardiomyocyte differentiation. We find that in the developing zebrafish heart, mRNA for a secreted Semaphorin (Sema), Sema3fb, is expressed by all cardiomyocytes, whereas mRNA for its receptor Plexina3 (Plxna3) is expressed by ventricular cardiomyocytes. In sema3fb CRISPR zebrafish mutants, ventricular chamber development is impaired; the ventricles of mutants are smaller in size than their wild type siblings, apparently because of differences in cell size and not cell numbers, with ventricular cardiomyocytes failing to undergo normal developmental hypertrophy. Analysis of chamber differentiation indicates defects in chamber specific gene expression at the border between the ventricular and atrial chambers, with spillage of ventricular chamber genes into the atrium, and vice versa, and a failure to restrict bmp4a mRNA to the atrioventricular canal. The disrupted atrioventricular border region in mutants is accompanied by hypoplastic heart chambers and impaired cardiac function. These data suggest a model whereby cardiomyocytes secrete a Sema cue that, through spatially restricted expression of the receptor, signals in a ventricular chamber-specific manner to establish a distinct border between atrial and ventricular chambers that is important for functional development of the heart.

Hox and Tale transcription factors in heart development and disease

2018 ◽  
Vol 62 (11-12) ◽  
pp. 837-846 ◽  
Author(s):  
Fabienne Lescroart ◽  
Stephane Zaffran
Keyword(s):  
Transcription Factors ◽  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Hox Genes ◽  
Heart Defects ◽  
First Year ◽  
First Year Of Life ◽  
Cardiac Mesoderm

Hox genes are highly conserved transcription factors with critical functions during development, in particular for patterning the antero-posterior axis of the embryo. Their action is very often associated with cofactors including the TALE family transcription factors. From Drosophila to vertebrates, Hox genes have been shown to have a major role in heart development. In this review, we focus on the increasing evidence implicating the anterior Hox genes and the Tale family members during heart development both in the cardiac mesoderm and in neural crest cells. Congenital heart defects are the leading cause of death in the first year of life and a better understanding of the role of Hox and Tale factors is highly relevant to human pathologies and will provide novel mechanistic insights into the underlying defects.

Understanding heart development and congenital heart defects through developmental biology: A segmental approach

2005 ◽  
Vol 45 (4) ◽  
pp. 107-118 ◽  
Author(s):  
Masahide Sakabe ◽  
Hiroko Matsui ◽  
Hirokazu Sakata ◽  
Katsumi Ando ◽  
Toshiyuki Yamagishi ◽  
...  
Keyword(s):  
Developmental Biology ◽  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Heart Defects ◽  
Segmental Approach

scholarly journals Rare Variants in NR2F2 Cause Congenital Heart Defects in Humans

2016 ◽  
Vol 98 (3) ◽  
pp. 592 ◽  
Author(s):  
Saeed Al Turki ◽  
Ashok K. Manickaraj ◽  
Catherine L. Mercer ◽  
Sebastian S. Gerety ◽  
Marc-Phillip Hitz ◽  
...  
Keyword(s):  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Rare Variants ◽  
Heart Defects

scholarly journals From Stripes to a Beating Heart: Early Cardiac Development in Zebrafish

2021 ◽  
Vol 8 (2) ◽  
pp. 17
Author(s):  
Cassie L. Kemmler ◽  
Fréderike W. Riemslagh ◽  
Hannah R. Moran ◽  
Christian Mosimann
Keyword(s):  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Heart Defects ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Zebrafish Model ◽  
Lateral Plate ◽  
Cardiac Progenitors

The heart is the first functional organ to form during vertebrate development. Congenital heart defects are the most common type of human birth defect, many originating as anomalies in early heart development. The zebrafish model provides an accessible vertebrate system to study early heart morphogenesis and to gain new insights into the mechanisms of congenital disease. Although composed of only two chambers compared with the four-chambered mammalian heart, the zebrafish heart integrates the core processes and cellular lineages central to cardiac development across vertebrates. The rapid, translucent development of zebrafish is amenable to in vivo imaging and genetic lineage tracing techniques, providing versatile tools to study heart field migration and myocardial progenitor addition and differentiation. Combining transgenic reporters with rapid genome engineering via CRISPR-Cas9 allows for functional testing of candidate genes associated with congenital heart defects and the discovery of molecular causes leading to observed phenotypes. Here, we summarize key insights gained through zebrafish studies into the early patterning of uncommitted lateral plate mesoderm into cardiac progenitors and their regulation. We review the central genetic mechanisms, available tools, and approaches for modeling congenital heart anomalies in the zebrafish as a representative vertebrate model.

scholarly journals Heart Development and Congenital Structural Heart Defects

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Lucile Houyel ◽  
Sigolène M. Meilhac
Keyword(s):  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Human Genetics ◽  
Current Knowledge ◽  
Phenotypic Diversity ◽  
Heart Defects ◽  
Annual Review ◽  
Publication Date ◽  
Research Perspectives

Congenital heart disease is the most frequent birth defect and the leading cause of death for the fetus and in the first year of life. The wide phenotypic diversity of congenital heart defects requires expert diagnosis and sophisticated repair surgery. Although these defects have been described since the seventeenth century, it was only in 2005 that a consensus international nomenclature was adopted, followed by an international classification in 2017 to help provide better management of patients. Advances in genetic engineering, imaging, and omics analyses have uncovered mechanisms of heart formation and malformation in animal models, but approximately 80% of congenital heart defects have an unknown genetic origin. Here, we summarize current knowledge of congenital structural heart defects, intertwining clinical and fundamental research perspectives, with the aim to foster interdisciplinary collaborations at the cutting edge of each field. We also discuss remaining challenges in better understanding congenital heart defects and providing benefits to patients. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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