Abstract
BackgroundCongenital heart diseases (CHDs) are the most common congenital anomalies with an estimated prevalence of 8 in 1000 live births. CHDs occur as a result of abnormal embryogenesis of the heart. Congenital heart diseases are associated with significant mortality and morbidity. The damage of the heart is irreversible due to a lack of regeneration potential, and usually, the patients may require surgical intervention. Studying the developmental biology of the heart is essential not only in understanding the mechanisms and pathogenesis of congenital heart diseases but also in providing us with insight towards developing new preventive and treatment methods.Main bodyThe etiology of congenital heart diseases is still elusive. Both genetic and environmental factors have been implicated to play a role in the pathogenesis of the diseases. Recently, cardiac transcription factors, cardiac-specific genes, and signaling pathways, which are responsible for early cardiac morphogenesis have been extensively studied in both human and animal experiments but leave much to be desired. The discovery of novel genetic methods such as next generation sequencing and chromosomal microarrays have led to further study the genes, non-coding RNAs and subtle chromosomal changes, elucidating their implications to the etiology of congenital heart diseases. Studies have also implicated non-hereditary risk factors such as rubella infection, teratogens, maternal age, diabetes mellitus, and abnormal hemodynamics in causing CHDs.These etiological factors raise questions on multifactorial etiology of CHDs. It is therefore important to endeavor in research based on finding the causes of CHDs. Finding causative factors will enable us to plan intervention strategies and mitigate the consequences associated with CHDs. This review, therefore, puts forward the genetic and non-genetic causes of congenital heart diseases. Besides, it discusses crucial signaling pathways which are involved in early cardiac morphogenesis. Consequently, we aim to consolidate our knowledge on multifactorial causes of CHDs so as to pave a way for further research regarding CHDs.ConclusionThe multifactorial etiology of congenital heart diseases gives us a challenge to explicitly establishing specific causative factors and therefore plan intervention strategies. More well-designed studies and the use of novel genetic technologies could be the way through the discovery of etiological factors implicated in the pathogenesis of congenital heart diseases.
Highlights
Embryogenesis of the heart The heart develops from the mesoderm [63]
[51], suggesting the monogenic inheritance model of Congenital heart diseases (CHDs) pathogenesis. This model of CHDs pathogenesis raises two important questions; firstly, why do we observe different CHDs phenotypes associated with the same type of single-gene mutations? Secondly, why do we observe the same kind of CHDs phenotypes in different single-gene mutations? These two questions suggest there might be many molecules involved in the etiology of CHDs
The questions remain if the CHDs mode of inheritance is a familial and whether its mode of inheritance is autosomal dominant or autosomal recessive. This enigma is highlighted by the fact that the autosomal dominant mutation is usually expressed in high penetrance, and we would expect the high percentage of first degree relatives to acquire the CHDs phenotypes, but the study indicates the opposite [56]
Summary
The multifactorial etiology of congenital heart diseases gives us a challenge to explicitly establishing specific causative factors and plan intervention strategies.
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