Chapter 062. Principles of Human Genetics (Part 1) ppsx

Chapter 062. Principles of
Human Genetics
(Part 1)

Harrison's Internal Medicine > Chapter 62. Principles of Human
Genetics
Impact of Genetics on Medical Practice
Impact of Genetics on Medical Practice: Introduction
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
technological 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. To date, the most significant impact of genetics has been to enhance
our understanding of disease etiology and pathogenesis. However, genetics is
rapidly playing a more prominent role in the diagnosis, prevention, and treatment
of disease (Chap. 64). 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. 65 and 67). Molecular genetics has already 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 modification of these peptides provides 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, maybe with the exception of simple trauma,
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. 64). A major current challenge is to elucidate the genetic components that
contribute to the pathogenesis of complex disorders. The recent publication of a
comprehensive catalogue of human single-nucleotide polymorphism (SNP)
haplotypes, the HapMap Project, provides an essential resource for genome-wide
association studies (see below).
Cancer has a genetic basis since it results from acquired somatic mutations
in genes controlling growth, apoptosis, and cellular differentiation (Chap. 79). 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 a great financial, social, and emotional burden on
society.
Genetics has historically focused 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 syndrome) can be diagnosed using cytogenetics (Chap. 63). Likewise,
many metabolic disorders (e.g., phenylketonuria, familial hypercholesterolemia)
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. 226

and 231). In neurology, genetics has unmasked the pathophysiology of a startling
number of neurodegenerative disorders (Chap. 360). 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. 99 and 110).
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.
379). 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. 74).
A similar phenomenon is emerging for genetically distinct forms of Alzheimer's
disease, several of which lead to the formation of neurofibrillary tangles (Chap.
365). 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 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 presently resides in computer 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 62-1). 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 62-1). The

ongoing refinement of bioinformatics is simplifying the access to this seemingly
daunting onslaught of new information.