The completion of the Human Genome Project in 2004 resulted in the initial sequencing of a reference human genome. This achievement ushered in a period of unprecedented growth in our understanding of the genetic underpinnings of human disease [1–3]. Recent advances have dramatically improved our knowledge of the genetic architecture of congenital heart disease (CHD), identifying important gene regulatory mechanisms [4–6]. The wealth of new putatively causative genes has had important implications for cardiac development [7, 8]. However, with these new discoveries came the growing realization of the enormous complexity of the human genome, especially as it relates to human CHD [9–11]. This emphasizes the importance of incorporating nuanced genetic features beyond coding sequence alterations in analyses [12–14]. Much of what now appears in the literature focuses on alterations in DNA sequence data that can be categorized and understood in terms of the size, character, location, or frequency of sequence variants, with important implications for gene expression and inheritance. Given what we know of the extreme phenotypic (both anatomic and physiologic) variability of CHD, even within narrow CHD anatomic subtypes, it is not surprising that the genetic underpinnings of CHD are complex and incompletely understood. The objective of this chapter is to provide some insight into known CHD inheritance patterns and recurrence risk and review the newest findings regarding the genetic basis of CHD. Rather than discuss a “laundry list” of identified genes and review basic Mendelian inheritance, we instead provide a conceptual framework for the relationship between genomic variation and CHD. We focus on clarifying recent studies that utilize the most recent genomic discovery techniques that may be difficult to interpret and are dependent upon a baseline knowledge of complex techniques. This overview aims to educate clinicians to analyze the pertinent genetic literature and understand the impact of new discovery. An updated list of commonly associated chromosomal aneuploidies, copy number variants, and putative causative genes are presented separately in Tables 2.1, 2.2, and 2.3 [10], but will not be discussed individually in any significant depth.

Common Variants

Although a single reference genome exists in theory, the 6 billion base diploid genome is characterized by diversity and ongoing polymorphic variations through subsequent generations. Any two unrelated genomes typically vary at millions of loci (a genetic position) totaling upward of 25 million base pairs of DNA [15, 16]. These genetic differences can be categorized as small‐scale, intermediate‐scale, or large‐scale structural variants (Tables 2.1, 2.2, and 2.3). Small‐scale structural variants are composed of single‐nucleotide changes and short insertions and deletions, called “indels.” Intermediate‐scale sequence variants can also be deletions, but more commonly refer to copy number variants (with gain or loss) that impact hundreds of thousands to millions of base pairs. Large‐scale structural variants refer to chromosomal abnormalities that can be evaluated microscopically. Each type of genetic variation will be described here. It is in this genetic variation that the key to both individuality as well as disease pathogenesis lies.

Essentially all of the methodology for genetic discovery used in the past decade is based upon the simple concept of identifying the genetic differences between patients and controls. One looks for either sequence variation or structural variation by selecting candidate genes to examine or compare the entire genome. The classical “forward genetic” approach begins with the identification of a phenotype, followed by various techniques to map the responsible gene. “Reverse genetics” takes the opposite approach, in which a gene of interest is mutated and the associated phenotype is interrogated. Although both techniques provide insight into causality, both also have limitations. Forward genetic approaches rely on statistical associations and may fail to provide robust mechanistic insights. Similarly, reverse genetic approaches provide a more robust association of gene function and phenotype, but until recently were not experiments that could be performed in humans and therefore lacked the complexity of other approaches. In general, if one wants to understand humans, it is necessary to study humans.

Prior to the sequencing of the human genome and the subsequent development of the International HapMap project, very little was known about the underlying contribution of genetic variation to CHD [17]. Although obvious associations between large chromosomal aneuploidies such as Trisomy 21 and CHD were well known (Table 2.1), the pedigrees of classic multigenerational families that were necessary to determine genetic linkage were simply not available. Except for relatively minor phenotypes such as atrial septal defects and familial patent arterial duct, cardiac‐related complications invariably led to death during childhood, thus preventing the accumulation of affected individuals in families [18, 19]. When data from the HapMap project became available in 2005, for the first time scientists had the tools to begin to understand the underlying genetic architecture of CHD as it is known today.

The HapMap was the first attempt to categorize the genetic diversity of humans using the millions of single‐nucleotide variants that are found throughout the human genome [17]. Large‐scale sequencing technology was limited to microarrays, so this map of genetic variants could be based only on sequence variation found commonly throughout the human population and was limited in resolution. These single‐nucleotide polymorphisms (SNPs) were usually found at a population frequency of at least 5%. Importantly, although 5% seems relatively infrequent, in genetic language it was the operational definition of a common variant at the time (now more often described as >1%). Studies that determined the association of common variation to complex traits or diseases were termed genome‐wide association studies (GWAS), and received a tremendous amount of interest as the first significant validation of the Human Genome Project [20]. GWAS specifically refer to studies involving common variants in contrast to the study of rare variants, which at the time was limited by technology. SNPs and common single‐nucleotide variants are one and the same, whereas rare single‐nucleotide variants that occur at very low frequencies, usually well below 1%, are considered mutations rather than polymorphisms or SNPs. In both candidate gene association studies and GWAS, the association of common variants and CHD is not strongly associated with CHD [21–24].

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Perioperative Care
2. Pediatric Heart Transplantation
3. Congenitally Corrected Transposition of the Great Arteries
4. Tetralogy of Fallot

Stay updated, free articles. Join our Telegram channel

Join

Tags: Pediatric Cardiac Surgery

May 18, 2023 | Posted by admin in CARDIOLOGY | Comments Off on Genetics of Congenital Heart Disease

Full access? Get Clinical Tree

Get Clinical Tree app for offline access

Get Clinical Tree app for offline access

Gene	Protein	Phenotypes*
ANKRD1	Ankyrin repeat domain	TAPVC
CITED2	c‐AMP responsive element‐binding protein	ASD; VSD
FOG2/ZFPM2	Friend of GATA	TOF, DORV
GATA4	GATA4 transcription factor	ASD, PS, VSD, TOF, AVSD, PAPVC
GATA6	GATA6 transcription factor	ASD, TOF, PS, AVSD, PDA, OFT defects, VSD
HAND2	Helix‐loop‐helix transcription factor	TOF
IRX4	Iroquois homeobox 4	VSD
MED13L	Mediator complex subunit 13‐like	TGA
NKX2‐5/NKX2.5	Homeobox containing transcription factor	ASD, VSD, TOF, HLH, COA, TGA, DORV, IAA, OFT defects
NKX2‐6	Homeobox containing transcription factor	PTA
TBX1	T‐Box 1 transcription factor	TOF, (22q11 deletion syndromes)
TBX5	T‐Box 5 transcription factor	AVSD, ASD, VSD (Holt‐Oram syndrome)
TBX20	T‐Box 20 transcription factor	ASD, MS, VSD
TFAP2B	Transcription factor AP‐2 beta	PDA (Char syndrome)
ZIC3	Zinc finger transcription factor	TGA, PS, DORV, TAPVC, ASD, HLH, VSD, dextrocardia, L–R axis defects
ACVR1/ALK2	BMP receptor	AVSD
ACVR2B	Activin receptor	PS, DORV, TGA, dextrocardia,
ALDH1A2