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Individual living organisms are unique because their genes harbor a unique code of DNA. Human genetics explores variation, evolution, and deviation from “normal” genetic structure and function. Medical genetics is the study of genetic diseases caused by changes that can involve entire chromosomes or much smaller regions, even single nucleotides. Its application in medicine encompasses all disciplines, as genetic diseases may affect multiple organs, often in the same individual.

Genetic cardiovascular diseases include chromosomal disorders (ie, congenital heart defects, congenital heart disease [CHD]), single-gene or monogenic diseases (ie, cardiomyopathies [CMPs], heritable aortic diseases), and multigenic/multifactorial disorders (ie, ischemic heart disease [IHD], atherosclerosis, diabetes). They may occur in the context of syndromes or exclusively involve the heart (ie, CMPs) or vessels (ie, heritable aortopathies). The burden of monogenetic cardiovascular diseases is difficult to establish. Some cardiac genetic diseases are common (ie, hypertrophic cardiomyopathy [HCM], some CHD), whereas others are extremely rare (pure restrictive cardiomyopathy [RCM], arterial tortuosity syndrome); however, most of them demonstrate clinical and genetic heterogeneity. This chapter provides a short summary of the classification of genetic diseases1 and the clinical and molecular genetic workup in cardiovascular diseases. It revises the clinical and molecular genetics of major and emerging groups of genetic cardiovascular diseases, highlighting disease-specific genetic needs.


Chromosomal Disorders

Chromosomal disorders occur when there is a gain or loss of chromosomes, or parts of them. Several chromosomal abnormalities are associated with cardiovascular diseases, both syndromes with cardiovascular involvement and heart defects as unique phenotypes. The three major categories of chromosomal disorders are:

  1. Those that involve the number of autosomes,2 typically trisomy 21 (or Down syndrome) that commonly shows atrioventricular septal defects

  2. Those that are caused by structural abnormalities of autosomes, typically translocations of large segments of chromosomes, as well as smaller insertions, deletions, or rearrangements, such as in 22q11 deletion syndromes that are associated with different CHDs3

  3. Those that involve the sex chromosomes, typically Turner syndrome in females that in the classic form carries a unique X chromosome (45,X).4 In addition to the typical traits of the syndrome (short stature, webbed neck, and incomplete or absent development of secondary sex characteristics, leading to infertility), this syndrome often manifests with bicuspid aortic valve, aortic coarctation and aortic aneurysm.

Single-Gene Diseases: Mendelian Inheritance

Single-gene diseases are caused by mutations affecting a specific gene. The vast majority of genetic cardiovascular diseases are inherited according to Mendelian rules.1 Based on inheritance pattern, they can be divided into autosomal dominant (AD), autosomal recessive (AR), or X-linked (XL) diseases (Fig. 9–1).


A to E, Mendelian inheritance, and F, maternal or matrilineal transmission. A. Autosomal dominant (AD) dilated cardiomyopathy (DCM) with conduction disease; in this family all mutation carriers are affected. The p.(Arg190Trp) is a ...

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