Complex Genetics and the Etiology of Human Congenital Heart Disease

Abstract

Congenital heart disease (CHD) is the most common birth defect. Despite considerable advances in care, CHD remains a major contributor to newborn mortality and is associated with substantial morbidities and premature death. Genetic abnormalities appear to be the primary cause of CHD but identifying precise defects has proven challenging, principally because CHD is a complex genetic trait. Due largely to recent advances in genomic technology such as next-generation DNA sequencing, scientists have begun to identify the genetic variants underlying CHD. In this chapter, the roles of modifier genes, de novo mutations, copy number variants, common variants and non-coding mutations in the pathogenesis of CHD are reviewed.

A Tbx5 Nonsense Mutation in Siblings With Divergent Phenotypes Associated With Isolated Septal Defects

“…HSD are the most common structural cardiac malformations affecting approximately 1% of live-born and accounts for 50% of congenital heart defects (CHDs). Various epidemiological studies have demonstrated that CHDs have a genetic predisposition as observed in most of the cases [1,2]. Especially, transcription factor genes, primarily NKX2-5, GATA4, and TBX5 have been implicated in regulating the septal development during prenatal stages [3].…”

Understanding the epigenetic origins of congenital heart disease may lead to its control

“…With clear insight into its aetiology, we may begin to dream of the ways to reduce the incidence of CHD. (8) But here is an exciting new prospect that we, as clinicians, should advocate: to encourage the further elucidation of those factors in the social environments of our patient populations that may be deleterious to heart development, and encourage the introduction of proven factors that reduce the incidence of CHD. In a resource-limited society, social upliftment may be our strongest epigenomic medicine!…”

“…(8,10) In the majority, the heart defect is solitary (or sporadic), thus the only congenital defect in a non-syndromic child with no known family history. Until recently these heart defects have posed an enigma: what is the exact cause of the isolated heart lesion when a search for a causative gene often proves to be futile?…”

“…(8) The crux lies in the realisation that it may be the control of heart development that is perturbed, rather than the structural, protein-coding genes per se.…”

“…(8) The most common ( Figure 2) are those of chromosomal defects linked to a specific set of heart defects. Some examples include Down syndrome with endocardial cushion defects, the 22q11.2 deletion syndrome with conotruncal lesions, Turner syndrome with coarctation of the aorta, and Williams syndrome with pulmonary and aortic root stenosis.…”