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ESSENTIALS OF GENETIC DISORDERS

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Genetic factors play a significant role in almost all cardiovascular disorders. Genetic defects are responsible for malformations of the heart and blood vessels, which account for the largest number of human birth defects. The estimated incidence of congenital heart disease is approximately 1% of all live births.1 The prevalence is estimated to be 10-fold higher among stillbirths.2 Genetic defects are responsible for familial cardiovascular disorders, such as cardiomyopathies, the long QT (LQT) syndromes, as well as sporadic forms of such disorders. Over 3600 genes have been identified to date for single-gene disorders with Mendelian patterns of inheritance. Likewise, genetic factors predispose to common complex phenotypes, such as atherosclerosis and hypertension. Over 4000 loci have been mapped for complex phenotypes. Molecular genetic studies provide the opportunity to decipher the genetic basis and pathogenesis of many disorders, especially cardiovascular diseases. Genetic discoveries have the potential to lead to identification of new targets for the prevention and treatment of human diseases. This is best illustrated in the case of PCSK9 gene, which was genetically mapped in 2003 as a cause of autosomal dominant hypercholesterolemia.3 Recently, the discovery led to subsequent development of PCSK9 inhibitors (evolocumab and alirocumab), which are highly effective for treatment of certain forms of hypercholerolemia.4,5 Partial deciphering of the genetic basis of cardiovascular disease has also ushered in routine genetic testing for various diseases, leading to an accurate genetic-based diagnosis and intervention. Given the rapid pace of genetic discoveries, it is expected that genetic diagnosis and genetic-based interventions will become incorporated into standard practice of medicine in the future. Thus, this chapter provides an overview of the genetic principles, and discusses the genetic basis for cardiovascular disorders as well as the medical and ethical implications of genetic findings.

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The Human Genome

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A genome is the complete set of the genetic material of each cell or individual: the nuclear and the mitochondrial genomes. The nuclear genome is composed of 3.2 billion base pairs. There are four types of nucleotides in each genome, two of which are purine (adenine, guanine) and two are pyrimidine (cytosine, thymine). The nuclear genome is distributed among 22 pairs of double-stranded autosomal chromosomes and two sex chromosomes (XX in females and XY in males). The sizes of chromosomes vary, with chromosome 1 being the largest at ~250 million base pairs and chromosome 21 the smallest at 48 million base pairs. The nuclear genome contains approximately 20,000 protein-coding genes.6 A gene has a 5′ transcriptional regulatory region, exons (which contain the protein coding sequence), introns (which are the intervening regions between exons), and the 3′ untranslated region (Fig. 55–1). The nuclear genome also contains several thousands of non–protein-coding genes that get transcribed into noncoding ribonucleic acids (RNAs) including microRNAs and long-noncoding RNAs. About 1% of the genome, which is approximately 300 million base pairs, code for the proteins. More than 50% ...

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