The errors of the DNA replication machinery might result in an excess or deficiency of a whole chromosome or a large fragment of chromosome. The most common form of chromosomal abnormalities is aneuploidy, which is defined as the absence or excess of a whole chromosome. A large number of chromosomal abnormalities affect the heart, typically resulting in various forms of congenital heart defects. Notable examples are Down syndrome, which is caused by trisomy of chromosome 21, and Turner syndrome, which is caused by monosomy of the X chromosome. The heart is involved in approximately half of the patients with Down syndrome and the typically abnormalities are atrioventricular canal defect, ventricular septal defects, atrial septal defects and tetralogy of Fallot.

Chromosomal abnormalities other than aneuploidy include duplication, deletion and rearrangements of chromosomal segments, which might result in CNVs. CNVs might affect gene function and increase susceptibility to or lead to a disease. Rare CNVs in genes involved in cardiac development are associated with sporadic forms of congenital heart defects [12]. Similarly, CNVs in SREBP1 and TLR4 genes are associated with plasma lipoproteins levels [13].

A single-gene disease is caused by a variant with a large effect size and occasionally by two variants in a single gene. The presence of the causal variant is sufficient and necessary to cause the phenotype. However, expression of the phenotype and its severity of also affected by various other determinants. Therefore, the phenotype in a single gene disorders is also polygenic and complex. Given that a very small number of variants in the genome have a very large effect sizes, single gene disorders are uncommon and comprise only a minority of the cardiovascular diseases. However, because of a very large effect of the causal DSV on the phenotype, single gene disorders exhibit a clear Mendelian pattern of inheritance, commonly an autosomal dominant pattern. In single gene disorders with an autosomal pattern of inheritance only one parent is heterozygous for the mutant variant and passes on the variant to half of the offspring. In such pedigree half of the relative family members are at the risk of developing the clinical phenotype. Recessive single gene disorders are caused by mutations in both copies of the responsible gene. In single gene disorders with a recessive pattern of inheritance, both parents are heterozygous for the variant. Therefore, in a given family, only 25 % of the offspring are homozygous for the mutant variants and exhibit the phenotype. Half of the offspring are heterozygous for the variant and do not show the clinical phenotype and 25 % only carry the wild type (normal) allele. Mutations in the X chromosome also could cause single gene disorders, which typically exhibit a phenotype only in males but a dominant variant also can cause a phenotype in heterozygous female offspring as well.

The vast majority of cardiovascular diseases are caused by the cumulative effects of a large number of DSVs, each imparting a small contribution to expression of the phenotype and hence, such diseases are polygenic. As in the monogenic disorders, in addition to the etiological genetic variants, other factors, such as the epigenetics and the environmental factors also contribute to expression of the phenotype. In view of the multifarious nature of etiological determinants, the presence of the risk DSVs is not sufficient to cause the phenotype nor does its absence prevent the disease. There is also no clear inheritance pattern despite evidence for familial aggregation of the phenotype. The common cardiovascular diseases such as atherosclerosis and hypertension are polygenic in nature.

This group of disorders primarily causes atherosclerosis through influencing plasma level of lipids. Table 27.1 lists single gene disorders that are known to cause atherosclerosis primarily through influencing cholesterol biosynthesis and metabolism. In addition, rare familial forms of CAD with an autosomal dominant inheritance pattern also have been described [14, 15]. In one family, the phenotype was mapped to chromosome 15q26.3. The putative causal variant is a rare 21-base pair deletion in exon 7 of MEF2A gene, which deletes seven amino acids from the protein [16]. Similarly, a p.R611C mutation in the LRP6 gene was identified in an Iranian family with premature coronary artery disease and low bone density [15].

CAD is a complex heritable trait, as indicated by familial aggregation of the disease. The risk of CAD increased by an approximately 2-fold in the first- and second-degree relatives of an affected individual [17, 18]. Despite the recognition of the genetic pre-disposition to CAD for several decades, elucidation of its genetic etiology had to await the development of modern molecular genetic techniques including high throughput genome-wide high-density genotyping, which facilitated the genome-wide association studies (GWAS). The GWAS, which compare the frequencies of a very large number of common DSVs in a large number of cases and controls, have led to identification of over 100 susceptibility loci for CAD (Table 27.2) (www.​genome.​gov/​gwastudies/​). Variants identified through GWAS, by design, are known and common variants, which are typically located within introns or intergenic regions (Table 27.2). Only a few of the variants identified through the GWAS are missense variants and hence, potentially functional. The vast majority of the variants does not seem to have a clear biological function and might simply be in linkage disequilibrium (co-segregating) with the true susceptibility allele on the same chromosome. Several of the genes identified through GWAS code for proteins related to the traditional risk factors for CAD, such as the lipoproteins. However, a large number of the candidate susceptibility genes identified have not been implicated in the pathogenesis of atherosclerosis. Thus, such loci, once replicated and validated, offer the opportunity to discover novel mechanisms independent of the traditional risk factors for CAD. This is a major strength of GWAS, as the new findings are not influenced by a priori knowledge but are based on an unbiased survey of the genome.