Download Classification of Genetic Disorders

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Classification of
Genetic Disorders
Dianna M. Milewicz
Chromosomal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 2551
Single-Gene Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 2552
Multifactorial Inheritance. . . . . . . . . . . . . . . . . . . . . . . . 2553
Key Points
for each human chromosome. Approximately 350 to 500
bands are identifiable on the chromosomes using this technique. Morphologically, chromosomes consist of two chromatids joined at the centromere, or central constriction. The
centromere divides the chromosome into the long arm, designated q, and the short arm, designated p. Chromosomal
morphology and staining allow the identification of the 22
homologous chromosomes and the two sex chromosomes
(XX or XY), termed a karyotype (Fig. 120.2).
Chromosomal disorders result from an excess or deficiency of whole chromosomes or portions of chromosomes.
There are many documented numeric and structural abnormalities in chromosomes in the human karyotype, and many
of these are associated with cardiovascular disease, including Down syndrome (trisomy of chromosome 21) and velocardiofacial syndrome (chromosomal microdeletions in the
q11 band of chromosome 22).1 The major chromosomal disorders associated with cardiovascular disease lead primarily
to congenital heart disease.
Aneuploidy is the most common and clinically significant type of chromosomal disorder. Aneuploidy exists when
an entire chromosome is missing or when there is an extra
chromosome, which means an abnormal number of chromosomes are found on karyotype analysis. Most patients with
aneuploidy have trisomy or an extra chromosome (resulting
in three homologous chromosomes rather than two). Monosomy, or the loss of an entire chromosome (resulting in only
one chromosome of a homologous pair), occurs less often.
Abnormalities of chromosome structure involve chromosomal rearrangement caused by chromosome breakage followed by reconstitution in an abnormal form. Structural
rearrangements can involve one or two chromosomes and
can retain a complete complement of genetic material (which
usually doe not result in a clinical phenotype) or can lead to
the loss (deletion) or gain (duplication) of chromosomal material. Typically, duplication, or gain, of portions of human
chromosomes is less harmful clinically than is the loss of
genetic material.
Contiguous-gene syndromes are disorders caused by
microduplications or deletions of chromosomal segments
• Single-gene disorders are caused by mutations of specific
genes in the human genetic material.
• Polymorphic changes are variations in the genetic
material that do not cause disease but may increase an
individual’s susceptibility to a particular disease.
• X-linked disorders are caused by an inheritance of a
mutant gene found in the X chromosome.
• Common diseases of adults, such as coronary artery
disease, hypertension, diabetes, and some congenital
malformations, are not inherited as a single-gene disorder
or a chromosomal abnormality.
Chromosomal Disorders
Genetic material is packaged within the nucleus of the cell
in nuclear material termed chromatin. When a cell divides,
the genetic material in the nucleus condenses into rod-shaped
structures known as chromosomes. The total human DNA
material is packaged into 46 chromosomes. The 46 chromosomes include 22 pairs of alike, or homologous, chromosome
(homologs) called autosomes and two sex chromosomes, X
and Y. Females have two X chromosomes (XX) and males
have an X and a Y chromosome (XY). Each chromosome has
a characteristic size and shape that allows the numbering
and identification of individual chromosomes.
The study of chromosome structure and inheritance is
called cytogenetics (Fig. 120.1). Cells for chromosomal analysis must be able to divide in culture, which limits the analysis of human chromosomes to a few cell types. Included in
the cells available for study are T lymphocytes collected
from the peripheral blood and stimulated to divide with
phytohemagglutinin, fibroblasts explanted from skin biopsies and maintained in culture, bone marrow cells, and
amniocytes. The chromosomes of a dividing cell are most
easily analyzed at the metaphase or the prometaphase-3
stage of mitosis, or cell division. The chromosomes are
stained, most typically with Giemsa banding, or G-banding,
resulting in a pattern of light and dark bands that is unique
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but some of the disorders can be inherited in an autosomal
dominant manner.
Chromatids
Telomere
Short arm (p)
Single-Gene Disorders
Centromere
Long arm (q)
Telomere
FIGURE 120.1. Diagram of chromosome structure. Chromosomal
structure is based on the position of the centromere, which divides
the chromosome into a short arm, designated p, and long arm, designated q. Pictured is a submetacentric chromosome, in which the
centromere is not the center. Chromosomes can also be metacentric, when the centromere is at the end of the chromosome. The ends
of the chromosome are called the telomeres. Chromatids are the two
identical strands of a chromosome connected at the centromere.
involving genes linked together on the chromosome. Some
contiguous-gene syndromes can be recognized by routine
cytogenic techniques. Other syndromes are not visible when
such techniques are used, so detection requires high-resolution chromosome analysis or studies using fluorescent in
situ hybridization. Typically, these syndromes are sporadic,
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A
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B
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10
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12
16
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C
13
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E
D
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F
21
22
G
X
Y
FIGURE 120.2. Picture of a human karyotype. Human chromosomes were prepared from a peripheral blood lymphocyte culture
arrested in prometaphase and stained by the Giemsa banding
method. Chromosomes were then arranged into the 22 pairs of
autosomal chromosomes and the pair of sex chromosomes (XX).
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Single-gene disorders are caused by mutations of specific
genes in the human genetic material. Human chromosomes
contain an estimated 50,000 to 100,000 genes coding for a
variety of proteins and RNAs that serve specific functions
in cells and tissues. These disorders follow the patterns of
inheritance originally identified by Mendel in his studies of
garden peas (mendelian inheritance). At present, over 10,000
single-gene disorders that are inherited in a mendelian
manner have been identified. A genetic locus is a specific
location on a chromosome, often used to refer to a certain
gene.2 Alleles are alternative forms of a locus or a gene.
An individual with two alike alleles at a given gene is
homozygous. If the alleles are different, the individual is
heterozygous at the locus.
Changes at a given locus or gene may be benign. Polymorphic changes are variations in the genetic material that
do not cause disease but may increase an individual’s susceptibility to a particular disease. In contrast, changes in
DNA that do produce disease are termed mutations. Mutations in specific genes are the underlying causes of singlegene disorders. Disorders are said to be either autosomal or
X-linked, based on the chromosomal location of the mutant
gene. Autosomal single-gene disorders are caused by mutations in genes on one of the 22 pairs of nonsex chromosomes.
X-linked disorders are those caused by mutations on the X
chromosome. Dominant conditions are disorders in which a
clinical phenotype is expressed in the heterozygous state
(that is, the individual has one copy of a mutant gene and
one copy of a normal gene). Recessive conditions are disorders that manifest a clinical phenotype in the homozygous
state (that is, an individual must have two mutated genes to
have the disease). Table 120.1 provides examples of singlegene disorder with cardiovascular manifestations.
Autosomal dominant inheritance is expression of a clinical phenotype caused by a heterozygous mutant gene on an
autosomal chromosome. As shown in Figure 120.3, the
inheritance pattern is vertical (the disorder is passed from
one generation to the next generation). Both males and
females are affected, although the severity of the disorder can
be influenced by the sex of the affected individual. Male-tomale transmission occurs and helps to distinguish autosomal dominant inheritance from X-linked dominant
inheritance. An affected individual has a 50% chance of
passing the condition to any of his or her children. Unaffected family members do not pass the trait on to their children. Of the identified single-gene disorders diseases with
mendelian inheritance, the majority are inherited in an autosomal dominant fashion.2
A number of special characteristics are associated with
autosomal dominant inheritance. With classic autosomal
dominant inheritance, the affected individual usually has an
affected parent, but this is not true in all cases. Sporadic
cases (without a family history of the disorder) can arise in
dominant disorders through new mutations in the gene,
which causes the disorder. The term variable expression of
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TABLE 120.1. Single-gene disorders with major cardiovascular features
Name of disorder
Defective gene
Prevalence
Inheritance
Cardiovascular manifestation
Immotile cilia syndrome
(Kartagener’s syndrome)
DNAI111
DNAH512
1 : 40,000
AR
Situs inversus visceral
Jervell and Lange-Nielsen syndrome
Tuberous sclerosis
KVLQT113 mink
TSC114
TSC215
ENG16
ALK117
FBN118
Rare
1 : 10,000
AR
AD
Prolonged QT interval, arrhythmias
Cardiac rhabdomyomata
—
AD
1 : 10,000
AD
Rare
AR
Telangiectasias, arteriovenous fistulas, vascular
malformations
Thoracic aortic aneurysms, aortic dissections,
valvular disease
Peripheral pulmonary artery stenosis
Hereditary hemorrhagic telangiectasia
(Osler-Weber-Rendu disease)
Marfan syndrome
Arteriohepatic dysplasia (Alagille’s
syndrome)
JAG119
AD, autosomal dominant; AR, autosomal recessive; MVP, mitral valve prolapse.
a dominant disorder refers to different levels of the clinical
expression of a mutated gene. This variability can include
the type and severity of symptoms or the variation in the age
of onset of a disorder. Decreased penetrance of an autosomal
dominant condition is the lack of phenotypic expression of
a disease in an individual who has inherited the mutated
gene that causes the disease. The penetrance of dominant
disorders is determined by family or population studies of
different disorders and is influenced by the ability of clinical
or laboratory studies to detect the phenotype.
In autosomal recessive inheritance, the expression of a
clinical phenotype occurs only when an individual has
inherited, at a single locus, two genes that are mutated; the
affected individual has inherited a mutant gene from both
parents (Fig. 120.3). The parents are heterozygous for the
mutant gene and do not have the disease. They are called
carriers. The inheritance is horizontal rather than vertical
and tends to be limited to siblings within a family. If both
parents are carriers of a recessive disorder, they have a 25%
chance of passing on the disorder to their children. Males
and females are equally affected. Consanguinity, or mating
between people who are related, can be an underlying cause
of the presence of autosomal recessive diseases. Autosomal
recessive disorders are often caused by mutations in the
genes that encode for enzymes or that transport proteins.
X-linked disorders are caused by inheritance of a mutant
gene found on the X chromosome. Because males have only
one X chromosome, X-linked disorders are fully expressed in
males. Females have two X chromosomes, and therefore
expression of the disease is dependent on whether the mutated
gene is dominant or recessive. Diseases that are rarely
expressed in females are called X-linked recessive. X-linked
recessive disorders are restricted to males, and there is no
male-to-male transmission (Fig. 120.3). Females who carry
the mutant gene on one of their X chromosomes rarely
express the disease and are therefore carriers.
X-linked dominant disorders are expressed in both males
and females who inherit the X chromosomes with the mutant
gene. The pattern of inheritance is vertical, as in autosomal
dominant disorders. The distinguishing feature of X-linked
dominant disorders is that there is no male-to-male transmission of the condition (Fig. 120.3).
Multifactorial Inheritance
Common diseases of adults, such as coronary artery disease,
hypertension, diabetes, and schizophrenia, and some congenital malformations, such as clubfoot, cleft lip, neural tube
defects, and pyloric stenosis, demonstrate familial aggregation but are not inherited as a single-gene disorder or a
chromosomal abnormality. Instead, these disorders are
multifactorial genetic diseases, indicating that they are
caused by the interplay of multiple genes with multiple
Autosomal dominant
FIGURE 120.3. Mendelian patterns on inheritance.
Pedigree patterns for autosomal dominant, autosomal
recessive, X-linked recessive, and X-linked dominant
inheritance are shown.
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X-linked recessive
Autosomal recessive
X-linked dominant
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genetic factors. Multifactorial inheritance is due not to
changes in a single gene but to a combination of genetic
changes that predispose to or produce the disease. In the
most common disorders seen in adults, genetic factors predispose an individual to the disorder, but environmental
factors also influence its expression. Although these disorders tend to be familial, no distinct pattern of inheritance
can be determined. The risk that family members will
develop these disorders cannot be calculated as easily as it
can for single-gene disorders, but certain characteristics of
multifactorial inheritance help to predict the risk. Recurrence risks represent empiric risk figures and vary among
different families, but in general, affect only 5% to 10% of
first-degree relatives. The risk for first-degree relatives is
greater than the risk for second-degree relatives. The greater
the number of family members affected with the disorder,
the greater the risk that other family member will have the
disorder. The risk for relatives of an affected patient increases
as the frequency of occurrence of the disease in the more
general population decreases. The more premature the onset
of the disease or the more severe the malformation, the
greater the recurrence risk for family members. Finally, if
the disease is more common in one sex, the risk is higher for
relatives of patients of the less susceptible sex. A number of
common diseases with cardiovascular manifestations demonstrate multifactorial inheritance.
Coronary artery disease (CAD) is a well-studied adult
disorder caused by genetic factors in combination with a
strong environmental component, and it serves as a model
for the manner in which genetic factors influence complex
diseases. At one end of the genetic spectrum leading to this
disease is familial hypercholesterolemia (FH), an autosomal
dominant disease resulting from mutation in low-density
lipoprotein (LDL) receptor gene (LDLR).3,4 Familial hypercholesterolemia is an example of a single-gene disorder that
results in atherosclerosis. Coronary artery disease is due to
elevations in plasma LDL levels, thereby contributing to the
genetic basis of this common disease. Individuals heterozygous for the LDL receptor mutations are common in the
general population, with an estimated prevalence of 1 in 500.
In addition to genes that alter plasma lipoprotein levels
leading to CAD, one gene has been identified that causes
familial CAD inherited in an autosomal dominant manner
in the absence of alterations in plasma lipoproteins; mutations in MEF2A have been identified as a cause of mendelian
inheritance of CAD in families. MEF2A is a member of the
MEF2 family of nuclear transcription factors, and mutations
in this gene are found in up to 2% of patients with CAD.5,6
In addition to CAD rarely being inherited in families as
a mendelian trait, studies have demonstrated familial aggregation of CAD in families that had premature CAD without
a clear mode of inheritance.7,8 Studies among graduates of
Johns Hopkins Medical School demonstrated that CAD was
almost four times as common among siblings of individuals
with CAD as among siblings of persons without heart
disease.9 Familial aggregations of ischemic heart disease
were noted, especially in the families of the female patients,
the sex less commonly affected by CAD. Therefore, CAD
demonstrates many of the features associated with multifactorial inheritance, including familial aggregation without a
clear mode of inheritance and a higher risk for relatives of
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individuals with premature CAD and relatives of affected
females.
The genes that lead to familial aggregation in families
are genes that increase the risk for CAD and may or may not
cause disease based on other genes and environmental factors.
In contrast to mendelian inheritance of risk for CAD due to
mutations in genes, polymorphisms in genes, most commonly single nucleotide polymorphisms (SNPs), are the
alterations that lead to this increased susceptibility to
disease. Case control association studies are the most frequently used method to identify SNPs that increase an
individual’s susceptibility to CAD. In these studies, the frequencies of SNPs are determined in both the cases (individuals with CAD) and the controls (individuals of the same
ethnic background as the cases who do not have CAD). A
SNP is considered associated with this disease if the frequency of the SNP differs significantly between cases and
controls. These methods have been used to study a large
number of SNPs in genes hypothesized to cause CAD and
have identified a large number of possible susceptibility
genes for CAD. Many of these studies need further validation
or replication in other patient populations to verify the association. Recently, the technology for detection of SNPs associated with disease has become more rapid and cost-effective,
and the development of a high-density SNP map covering the
entire human genome has allowed case control association
studies to scan SNPs throughout the human genome.10
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