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Few areas of science and medicine are seeing advances
at the pace we are experiencing in the related fields of
genetics and genomics. It may appear surprising to
many students today, then, to learn that an appreciation
of the role of genetics in medicine dates back well over
a century, to the recognition by the British physician
Archibald Garrod and others that Mendels laws of
inheritance could explain the recurrence of certain clinical disorders in families. During the ensuing years, with
developments in cellular and molecular biology, the field
of medical genetics grew from a small clinical subspecialty concerned with a few rare hereditary disorders to
a recognized medical specialty whose concepts and
approaches are important components of the diagnosis
and management of many disorders, both common and
At the beginning of the 21st century, the Human
Genome Project provided a virtually complete sequence
of human DNAour genome (the suffix -ome coming
from the Greek for all or complete)which now
serves as the foundation of efforts to catalogue all
human genes, understand their structure and regulation,
determine the extent of variation in these genes in different populations, and uncover how genetic variation
contributes to disease. The human genome of any individual can now be studied in its entirety, rather than one
gene at a time. These developments are making possible
the field of genomic medicine, which seeks to apply a
large-scale analysis of the human genome and its products, including the control of gene expression, human
gene variation, and interactions between genes and the
environment, to medical care.


The Practice of Genetics
The medical geneticist is usually a physician who works
as part of a team of health care providers, including
many other physicians, nurses, and genetic counselors,
to evaluate patients for possible hereditary diseases.
They characterize the patients illness through careful
history taking and physical examination, assess possible
modes of inheritance, arrange for diagnostic testing,

develop treatment and surveillance plans, and participate in outreach to other family members at risk for the
However, genetic principles and approaches are not
restricted to any one medical specialty or subspecialty;
they permeate many, and perhaps all, areas of medicine.
Here are just a few examples of how genetics and
genomics are applied to medicine today:
A pediatrician evaluates a child with multiple congenital malformations and orders a high-resolution
genomic test for submicroscopic chromosomal deletions or duplications that are below the level of resolution of routine chromosome analysis (Case 32).
A genetic counselor specializing in hereditary breast
cancer offers education, testing, interpretation, and
support to a young woman with a family history of
hereditary breast and ovarian cancer (Case 7).
An obstetrician sends a chorionic villus sample taken
from a 38-year-old pregnant woman to a cytogenetics laboratory for confirmation of abnormalities in
the number or structure of the fetal chromosomes,
following a positive screening result from a noninvasive prenatal blood test (see Chapter 17).
A hematologist combines family and medical history
with gene testing of a young adult with deep venous
thrombosis to assess the benefits and risks of initiating and maintaining anticoagulant therapy (Case 46).
A surgeon uses gene expression array analysis of a
lung tumor sample to determine prognosis and to
guide therapeutic decision making (see Chapter 15).
A pediatric oncologist tests her patients for genetic variations that can predict a good response or an adverse
reaction to a chemotherapeutic agent (Case 45).
A neurologist and genetic counselor provide APOE
gene testing for Alzheimer disease susceptibility for a
woman with a strong family history of the disease
so she can make appropriate long-term financial
plans (Case 4).
A forensic pathologist uses databases of genetic polymorphisms in his analysis of DNA samples obtained
from victims personal items and surviving relatives
to identify remains from an airline crash.
A gastroenterologist orders genome sequence analysis
for a child with a multiyear history of life-threatening
and intractable inflammatory bowel disease. Sequencing reveals a mutation in a previously unsuspected


gene, clarifying the clinical diagnosis and altering

treatment for the patient (see Chapter 16).
Scientists in the pharmaceutical industry sequence
cancer cell DNA to identify specific changes in oncogenic signaling pathways inappropriately activated
by a somatic mutation, leading to the development
of specific inhibitors that reliably induce remissions
of the cancers in patients (Case 10).

Categories of Genetic Disease

Virtually any disease is the result of the combined action
of genes and environment, but the relative role of the
genetic component may be large or small. Among disorders caused wholly or partly by genetic factors, three
main types are recognized: chromosome disorders,
single-gene disorders, and multifactorial disorders.
In chromosome disorders, the defect is due not to a
single mistake in the genetic blueprint but to an excess
or a deficiency of the genes located on entire chromosomes or chromosome segments. For example, the presence of an extra copy of one chromosome, chromosome
21, underlies a specific disorder, Down syndrome, even
though no individual gene on that chromosome is
abnormal. Duplication or deletion of smaller segments
of chromosomes, ranging in size from only a single
gene up to a few percent of a chromosomes length, can
cause complex birth defects like DiGeorge syndrome or
even isolated autism without any obvious physical
abnormalities. As a group, chromosome disorders are
common, affecting approximately 7 per 1000 liveborn
infants and accounting for approximately half of all
spontaneous abortions occurring in the first trimester of
pregnancy. These types of disorders are discussed in
Chapter 6.
Single-gene defects are caused by pathogenic mutations in individual genes. The mutation may be present
on both chromosomes of a pair (one of paternal origin
and one of maternal origin) or on only one chromosome
of a pair (matched with a normal copy of that gene
on the other copy of that chromosome). Single-gene
defects often cause diseases that follow one of the classic
inheritance patterns in families (autosomal recessive,
autosomal dominant, or X-linked). In a few cases, the
mutation is in the mitochondrial rather than in the
nuclear genome. In any case, the cause is a critical error
in the genetic information carried by a single gene.
Single-gene disorders such as cystic fibrosis (Case 12),
sickle cell anemia (Case 42), and Marfan syndrome (Case 30) usually exhibit obvious and characteristic pedigree patterns. Most such defects are rare,
with a frequency that may be as high as 1 in 500 to

1000 individuals but is usually much less. Although

individually rare, single-gene disorders as a group are
responsible for a significant proportion of disease and
death. Overall, the incidence of serious single-gene disorders in the pediatric population has been estimated to
be approximately 1 per 300 liveborn infants; over an
entire lifetime, the prevalence of single-gene disorders is
1 in 50. These disorders are discussed in Chapter 7.
Multifactorial disease with complex inheritance
describes the majority of diseases in which there is a
genetic contribution, as evidenced by increased risk for
disease (compared to the general public) in identical
twins or close relatives of affected individuals, and yet
the family history does not fit the inheritance patterns
seen typically in single-gene defects. Multifactorial diseases include congenital malformations such as
Hirschsprung disease (Case 22), cleft lip and palate, and
congenital heart defects, as well as many common disorders of adult life, such as Alzheimer disease (Case 4),
diabetes, and coronary artery disease. There appears to
be no single error in the genetic information in many of
these conditions. Rather, the disease is the result of the
combined impact of variant forms of many different
genes; each variant may cause, protect from, or predispose to a serious defect, often in concert with or triggered by environmental factors. Estimates of the impact
of multifactorial disease range from 5% in the pediatric
population to more than 60% in the entire population.
These disorders are the subject of Chapter 8.

During the 50-year professional life of todays professional and graduate students, extensive changes are
likely to take place in the discovery, development, and
use of genetic and genomic knowledge and tools in
medicine. Judging from the quickening pace of discovery within only the past decade, it is virtually certain
that we are just at the beginning of a revolution in integrating knowledge of genetics and the genome into
public health and the practice of medicine. An introduction to the language and concepts of human and medical
genetics and an appreciation of the genetic and genomic
perspective on health and disease will form a framework
for lifelong learning that is part of every health professionals career.
Feero WG, Guttmacher AE, Collins FS: Genomic medicinean
updated primer, N Engl J Med 362:20012011, 2010.
Ginsburg G, Willard HF, editors: Genomic and personalized medicine
(vols 1 & 2), ed 2, New York, 2012, Elsevier.