The beginning of the new millennium was marked by the announcement that the vast majority of the human genome had been sequenced. This milestone in the exploration of the human genome was preceded by numerous conceptual and technologic advances. They include, among others, the elucidation of the DNA double-helix structure, the discovery of restriction enzymes and the polymerase chain reaction (PCR), the development and automatization of DNA sequencing, and the generation of genetic and physical maps by the Human Genome Project (HGP). The consequences of this wealth of knowledge for the practice of medicine are profound. First, the most significant impact of genetics has been to enhance our understanding of disease etiology and pathogenesis. However, genetics is playing an increasingly prominent role in the diagnosis, prevention, and treatment of disease (Chap. 63). Genetic approaches have proven invaluable for the detection of infectious pathogens and are used clinically to identify agents that are difficult to culture such as mycobacteria, viruses, and parasites. In many cases, molecular genetics has improved the feasibility and accuracy of diagnostic testing and is beginning to open new avenues for therapy, including gene and cellular therapy (Chaps. 68 and 67). Molecular genetics has significantly changed the treatment of human disease. Peptide hormones, growth factors, cytokines, and vaccines can now be produced in large amounts using recombinant DNA technology. Targeted modifications of these peptides provide the practitioner with improved therapeutic tools, as illustrated by genetically modified insulin analogues with more favorable kinetics. There is hope that a better understanding of the genetic basis of human disease will also have an increasing impact on disease prevention.
Genetics has traditionally been viewed through the window of relatively rare single-gene diseases. Taken together, these disorders account for ∼10% of pediatric admissions and childhood mortality. It is, however, increasingly apparent that virtually every medical condition has a genetic component. As is often evident from a patient's family history, many common disorders such as hypertension, heart disease, asthma, diabetes mellitus, and mental illnesses are significantly influenced by the genetic background. These polygenic or multifactorial (complex) disorders involve the contributions of many different genes, as well as environmental factors that can modify disease risk (Chap. 63). Genome-wide association studies (GWAS) have elucidated numerous disease-associated loci and are providing novel insights into the allelic architecture of complex traits. These studies have been facilitated by the availability of comprehensive catalogues of human single-nucleotide polymorphism (SNP) haplotypes generated through the HapMap Project.
Cancer has a genetic basis since it results from acquired somatic mutations in genes controlling growth, apoptosis, and cellular differentiation (Chap. 83). In addition, the development of many cancers is associated with a hereditary predisposition. The prevalence of genetic diseases, combined with their severity and chronic nature, imposes great financial, social, and emotional burdens on society.
Genetics has historically focused predominantly on chromosomal and metabolic disorders, reflecting the long-standing availability of techniques to diagnose these conditions. For example, conditions such as trisomy 21 (Down syndrome) or monosomy X (Turner's syndrome) can be diagnosed using cytogenetics (Chap. 62). Likewise, many metabolic disorders (e.g., phenylketonuria, familial hyper–cholesterolemia) are diagnosed using biochemical analyses. Recent advances in DNA diagnostics have extended the field of genetics to include virtually all medical specialties. In cardiology, for example, the molecular basis of inherited cardiomyopathies and ion channel defects that predispose to arrhythmias is being defined (Chaps. 233 and 238). In neurology, genetics has unmasked the pathophysiology of a startling number of neurodegenerative disorders (Chap. 366). Hematology has evolved dramatically, from its incipient genetic descriptions of hemoglobinopathies to the current understanding of the molecular basis of red cell membrane defects, clotting disorders, and thrombotic disorders (Chaps. 104 and 116).
New concepts derived from genetic studies can sometimes clarify the pathogenesis of disorders that were previously opaque. For example, although many different genetic defects can cause peripheral neuropathies, disruption of the normal folding of the myelin sheaths is frequently a common final pathway (Chap. 384). Several genetic causes of obesity appear to converge on a physiologic pathway that involves products of the proopiomelanocortin polypeptide and the MC4R receptor, thus identifying a key mechanism for appetite control (Chap. 77). A similar phenomenon is emerging for genetically distinct forms of Alzheimer's disease, several of which lead to the formation of neurofibrillary tangles (Chap. 371). The identification of defective genes often leads to the detection of cellular pathways involved in key physiologic processes. Examples include identification of the cystic fibrosis conductance regulator (CFTR) gene; the Duchenne's muscular dystrophy (DMD) gene, which encodes dystrophin; and the fibroblast growth factor receptor-3 (FGFR3) gene, which is responsible for achondroplastic dwarfism. Similarly, transgenic (over)expression, and targeted gene "knock-out" and "knock-in" models help to unravel the physiologic function of genes.
The astounding rate at which new genetic information is being generated creates a major challenge for physicians, health care providers, and basic investigators. The terminology and techniques used for discovery evolve continuously. Much genetic information resides in databases or is being published in basic science journals. Databases provide easy access to the expanding information about the human genome, genetic disease, and genetic testing (Table 61-1). For example, several thousand monogenic disorders are summarized in a large, continuously evolving compendium, referred to as the Online Mendelian Inheritance in Man (OMIM) catalogue (Table 61-1). The ongoing refinement of bioinformatics is simplifying the access to this daunting onslaught of new information.
Table 61-1 Selected Databases Relevant for Genomics and Genetic Disorders
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Table 61-1 Selected Databases Relevant for Genomics and Genetic Disorders
|National Center for Biotechnology Information (NCBI)||http://www.ncbi.nlm.nih.gov/|
Broad access to biomedical and genomic information, literature (PubMed), sequence databases, software for analyses of nucleotides and proteins
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