++
Genetic disorders and birth defects are sometimes perceived as
being so uncommon that the general pediatrician will seldom encounter them.
However, each day more than 400 babies with birth defects are born
in the United States, and 1 of every 5 infant deaths is caused by
these disorders. Virtually every medical condition, except for some
cases of trauma, is influenced by an individual’s genetic
background. Rapid advances in our knowledge of the genetic basis of
disease, coupled with emerging technologies for high-throughput
genetic testing, are also rapidly transforming the practice of medicine.
++
Comprehensive databases of factual information about the identification
of new disease genes, genotype–phenotype correlation, and the
availability of genetic testing have become widely available online
and in published review articles. Thus, each of the following sections
seeks to emphasize important fundamental concepts while providing paradigmatic
examples.
++
Traditionally, various human traits (eg, skin color, intelligence)
and disorders (eg, phenylketonuria, achondroplasia) have been divided
into those that are genetic versus those that are nongenetic, the
latter usually referring to disorders “determined” by
the environment (eg, infectious diseases, teratogens). However, this
dichotomy separating gene and environment is largely artificial,
and the distinction between the two has become increasingly blurred.
Disorders caused by mutations in a single gene (eg, cystic fibrosis,
sickle-cell disease) can be heavily influenced by the environment, and
diseases caused by the environment (eg, AIDS secondary to infection
with HIV-1) can be substantially modified by the presence of certain polymorphisms.
In other words, the cause of most diseases can be considered genetic
and environmental; some diseases are more strongly influenced by
genes, whereas others are more strongly influenced by the environment.
++
Whether defined narrowly or broadly, genetic disorders and birth
defects contribute substantially to morbidity and mortality in pediatric
patients. For example, the percentage of deaths attributable to
genetic disease in hospitals in the United Kingdom has risen from
16.5% in 1914 to 50% in 1976. Birth defects are
also the leading cause of death in infancy in the United States,
accounting for more than 20% of infant deaths. Cardiovascular
malformations are the leading cause of premature mortality from
congenital anomalies. This reflects a better understanding of the
etiology of pediatric diseases as well as the substantial reduction
in infectious disease and perinatal mortality during the 20th century.
Population-based studies suggest that birth defects and genetic
disorders account for about 10% of hospitalizations and
about 30% of all hospitalization charges. Approximately
7% of pediatric admissions are for single-gene and chromosomal
disorders, and another 15% to 20% for congenital
malformations of different types. Moreover, about 35% of
hospital deaths of children are caused by a genetic condition and/or
birth defect. Recent advances in therapeutics have substantially
prolonged the survival of children with birth defects and/or
genetic diseases, challenging practitioners to care for older children
and young adults with genetic disorders.
++
Classifications of genetic disorders depend, in part, on the
delineation of a phenotypic trait (eg, mental retardation, craniosynostosis)
and the judgment of whether this trait varies substantially from
a “normal” trait. Whether a trait should be considered
normal or abnormal (eg, a midline abdominal aorta, short digits)
is not always clear, and the decision may depend, in part, on findings
in other family members. Genetic disorders can be broadly classified
into several major groups: chromosome disorders, single-gene disorders,
multifactorial disorders, and disorders with nontraditional mechanisms of
expression and inheritance.
++
Chromosome disorders result from abnormalities of chromosome
number (ie, aneuploidy) and/or structure. These abnormalities include
duplications, deletions, rearrangements, extra chromosomes (trisomy),
and missing chromosomes (monosomy). Most chromosome disorders arise
de novo and are not transmissible. However, some chromosome disorders
are heritable because they are carried by an unaffected parent in
a state that does not cause disease (eg, balanced rearrangements)
but can be transmitted to an offspring to produce a state that does
cause disease (unbalanced rearrangement). Most conceptions with chromosome
abnormalities are terminated spontaneously early in gestation, and
chromosome abnormalities are the leading known cause of pregnancy
loss. Most individuals with chromosome disorders have major and/or
minor malformations, variable degrees of mental retardation, and/or
growth deficiency.
++
Disorders in which single genes have been altered are called monogenic
conditions. Single-gene disorders can be transmitted from
parent to offspring in autosomal-dominant or autosomal-recessive
patterns and thus are sometimes known as mendelian conditions. Single-gene
disorders can also be produced by new mutations in a single individual
that are appearing for the first time in a family; the mutation
has arisen de novo in the affected family member. Copies of genes
that have different sequences are referred to as alleles. A
gene’s location on a chromosome is termed a locus.
++
The four modes of inheritance of single-gene disorders are autosomal-recessive,
in which both copies of a gene at a single locus on an autosome
(nonsex chromosome) are altered; autosomal-dominant, in which only
one allele of a gene at a single locus on an autosome is altered;
X-linked recessive, in which one allele of a gene at a locus on
the X chromosome is altered in affected males and both alleles of
a gene at a locus on the X chromosome are altered in affected females;
and X-linked dominant, in which one allele of a gene at a locus
on the X chromosome is altered in affected males and females. Y-linked
inheritance is uncommon for genetic disorders.
++
Substantial progress has been made toward identifying the genes
that cause single-gene disorders. However, these conditions represent
only a small fraction of the total burden of genetic disease. Most
birth defects are not caused by alterations of a single gene or
chromosome, and many common pediatric disorders are influenced by
different combinations of alleles at various loci. Traits in which
variation is caused by the effects of many different genes are called polygenic. If
the variation of a polygenic trait is also affected by nongenetic
factors (eg, environmental variables), the terms multifactorial or complex are
often used to describe the trait. In contrast to single-gene disorders,
multifactorial traits are not transmitted in mendelian patterns. The
identification of the genetic and environmental determinants of
multifactorial traits is a major objective of genetic research.
++
Some genetic disorders do not segregate in the patterns expected
of single-gene conditions or multifactorial traits and are transmitted
from parent to offspring in nontraditional patterns of inheritance.
Disorders exhibiting nontraditional patterns of inheritance include those
caused by mutations in the mitochondrial genome, uniparental disomy
(two alleles from the same locus inherited from one parent instead
of both parents), and gene duplication. The expression of some conditions
is influenced substantially by whether the altered allele is transmitted
to a child by the mother or father, a so-called parent-of-origin
effect. Some genetic conditions exhibit a nontraditional pattern
of inheritance as a consequence of this parent-of-origin effect
and are relatively uncommon.
++
The terms congenital, hereditary, and familial are
not synonymous. Conditions that are present at birth are referred
to as congenital conditions, whether the major
risk factor is genetic or not. For example, infection with cytomegalovirus, clubfeet
caused by oligohydramnios, and trisomy 21 are all congenital conditions.
However, only trisomy 21 is clearly a genetic condition, and none
of these conditions are usually hereditary.
++
The term hereditary defines conditions that can
be transmitted from parent to offspring. All hereditary conditions
are genetic conditions, but not all genetic conditions are hereditary
(eg, most cases of trisomy 21). Conditions that appear to cluster
within families are frequently called familial conditions
and may include nongenetic conditions (eg, rotaviral or streptococcal infections)
as well as genetic conditions. Nevertheless, although all hereditary
conditions can be familial, not all genetic conditions are familial (eg,
most cases of trisomy 21). Distinguishing which term most appropriately
defines a condition facilitates diagnosis, management, and counseling
of families about the risk of recurrence of a condition.
++
The probability that an individual who possesses a disease-related
genotype (an individual’s allelic constitution at a single
locus is called a genotype) exhibits the disease
phenotype is called penetrance. When this probability
is less than 1, the disease is said to exhibit reduced (or incomplete)
penetrance. Penetrance levels are usually estimated by examining
a large number of families and determining what proportion of the
obligate carriers (ie, those individuals who have an affected parent
and an affected child and thus must be carriers of the altered gene)
or obligate homozygotes (in the case of autosomal-recessive disorders)
develop the disease phenotype. Retinoblastoma is a good example
of a genetic condition in which reduced penetrance is observed.
Family studies have demonstrated that about 10% of obligate
carriers of a mutation in the retinoblastoma susceptibility gene do
not develop a retinoblastoma. The penetrance of the condition is
thus about 90%.
++
Individuals with the same genetic condition or even the same
genotype can have substantially different phenotypes. This is called variable
expressivity. For example, within the same kindred, one
sibling with neurofibromatosis type 1 (NF1) may have café au
lait spots, axillary freckling, and sphenoid wing dysplasia, and
another sibling with NF1 has café au lait spots, a plexiform
neurofibroma, and pseudarthrosis of the tibia. Although each sibling
has the same genotype, the expression of the NF1 phenotype is different
between them.
++
Variable expressivity may be explained by the influence of other
genes (ie, modifying genes), environmental factors (eg, earlier
palliative intervention), or random variation. Variable expressivity
among families is sometimes related to the presence of different
genotypes. The causation of a disease phenotype by a variety of
different genotypes at the same locus is called allelic
heterogeneity. A potentially powerful strategy to provide
affected individuals with better anticipatory guidance is to estimate the
correlation between genotypes and specific phenotypic characteristics
(genotype-phenotype correlation studies). The compilation of findings
from many individuals with a genetic condition defines the distribution
of phenotypic variation of a disorder. Although not every affected
individual will have the same findings, variable expressivity is
often confused with reduced penetrance. The absence of a disease phenotype
in an obligate carrier (ie, reduced penetrance) is not considered
variable expression of the condition.
++
Genes that have more than one discernible effect on the phenotype
are said to be pleitropic. A good example of a
gene that has pleiotropic effects is the cystic fibrosis
transmembrane regulator(CFTR). CFTR encodes
a protein that forms cyclic-AMP–regulated chloride ion
channels that span the cell membrane of specialized epithelial cells
such as those that line the lungs and bowel. Mutations in CFTR result
in abnormalities of the lungs, pancreas, and sweat glands. Other
examples of genetic conditions that result from mutations in genes
with pleiotropic effects include Marfan syndrome (characterized
by ocular, cardiovascular, and skeletal defects) and osteogenesis
imperfecta, in which the bones, teeth, and sclerae are affected.
Thus pleiotropy can be caused by genes whose products play similar roles
in different tissues and organs. Pleiotropy can also be caused by
genes whose protein products play varied roles in different developmental programs.
For example, individuals with campomelic dysplasia have a skeletal
dysplasia that is sometimes accompanied by sex reversal. Campomelic
dysplasia is caused by mutations in a gene called SRY-related
HMG-BOX 9 (SOX9), which plays an important
regulatory role in skeletal development and sexual differentiation.
++
Some genetic conditions seem to display an earlier age of onset
and/or more severe expression in the more recent generations
of a pedigree. This effect is called anticipation. Some investigators
had proposed that anticipation was an artifact of better observation
and diagnostic tools available to the contemporary clinician: a
disorder previously diagnosed at age 60 might now be diagnosed at
age 40. Within the past 10 years, it has been demonstrated that for
some disorders, anticipation has a biological basis. One of the
best examples of anticipation comes from studies of myotonic dystrophy
(DM), the most common muscular dystrophy that affects adults. Myotonic
dystrophy is characterized by progressive deterioration of skeletal
muscle, cardiomyopathy, testicular atrophy, and cataracts and is
caused most often by mutations in a gene on chromosome 19 that encodes
a protein kinase. Analysis of this gene has demonstrated that myotonic
dystrophy is caused by the expansion of a CTG repeat in the 3' untranslated
region of the gene (ie, a region transcribed into mRNA but not translated
into protein). Unaffected individuals have 5 to 30 copies of the repeat;
mildly affected individuals may have 50 to 100 copies of the repeat;
and severely affected individuals may have 100 to more than several
thousand repeats. The number of repeats is positively correlated
with the severity of the disease. Furthermore, the number of repeats
often increases with succeeding generations, which have more severe
disease compared to preceding generations.
+++
Autosomal-Dominant Disorders
++
For autosomal-dominant conditions, the presence of only one copy
of an altered allele at a locus is sufficient to produce a disease
phenotype. Genetic disorders that are inherited in an autosomal-dominant
pattern are the most common single-gene disorders described in humans. Individually,
however, each autosomal-dominant disorder is relatively uncommon.
Thus, most affected offspring are produced from the mating of an
affected parent and an unaffected parent or from a de novo mutation.
A parent affected with an autosomal-dominant disorder can transmit
either the normal or altered allele to his or her offspring. Each
of these events has a probability of 0.5. Thus, on average, half
of the children will be heterozygous for the altered allele and
express the disease, and half will be homozygous for a normal allele.
Matings between individuals affected by the same autosomal-dominant
disorder are rare.
++
An idealized pedigree for autosomal-dominant inheritance (Fig. 170-1) illustrates several important
characteristics: First, the two sexes exhibit the trait in approximately
equal proportions, and males and females are equally likely to transmit
the trait. Second, no generation is skipped. Every individual with
the trait has an affected parent. Third, father-to-son transmission
is observed. Although father-to-son transmission is not required
to establish autosomal-dominant inheritance, its presence excludes
some other modes of inheritance (eg, X-linked and mitochondrial).
Last, an affected individual transmits the trait to half of her
or his offspring, on average.
++
++
De novo mutations are an important cause of autosomal-dominant
conditions. For autosomal-dominant conditions that are lethal in
prereproductive age (eg, thanatophoric dysplasia), de novo mutations
are the most common cause of the disorder. For some autosomal-dominant
conditions (eg, achondroplasia, Marfan syndrome) the age of the
father and the likelihood of transmitting a new mutation to his
offspring are positively correlated. Sometimes, clearly unaffected parents
have more than one child affected with an autosomal-dominant disorder.
Recent studies have demonstrated that one of the parents in such families
has two or more different cell lines in his or her germ cells (cells
that produce sperm or eggs)—with at least one cell line
containing an altered allele. This phenomenon is called germ-line
mosaicism. Germ-line mosaicism appears to be much more
common for some disorders (eg, osteogenesis imperfecta) and is another
cause of autosomal-dominant conditions that are lethal in prereproductive
age. Two or more cell lines can also be found in the somatic cells
of an individual (somatic mosaicism). Individuals with somatic mosaicism
may have all the same characteristics found in affected individuals,
exhibit abnormalities limited to only tissues containing the mutant
cell line, or appear unaffected.
+++
Autosomal-Recessive Disorders
++
For autosomal-recessive conditions, the presence of two copies
of an altered allele at a locus is required to produce a disease phenotype.
Genetic disorders that are inherited in an autosomal-recessive pattern
are less common than autosomal-dominant disorders in most populations.
However, heterozygous carriers for recessive conditions are much more
common than affected homozygotes. Thus the parents of individuals
affected with autosomal-recessive conditions are usually heterozygous
carriers. For example, the prevalence of cystic fibrosis is approximately
1 in 2500 in northern European populations. The Hardy-Weinberg law
states that population frequencies of genotypes can be predicted
on the basis of gene frequencies in a randomly mating population
(random mating is also referred to as panmixia).
Suppose that at a two-allele locus, the frequency p of
an allele A is 0.70. Then 70% of the sperm
and egg cells in a population have this allele. Because the sum of
allele frequencies at a locus must equal 1, the frequency q of
the allele a is equal to 1 – p = q or
1.0 – 0.7 = 0.3. Under panmixia the probability
that a sperm carrying allele A unites with an egg
carrying allele A is p × p = p2 or
0.7 × 0.7 = 0.49 (multiplication
rule). This is the probability of producing an offspring with the
AA genotype. The probability of producing an offspring with the
aa genotype is q × q = q2 or
0.3 × 0.3 = 0.09.
++
Heterozygotes can be produced two different ways. A sperm carrying
allele A can unite with an egg carrying allele a, or
a sperm carrying allele a can unite with an egg
carrying allele A. Thus, the frequency with which
this occurs is equal to the product of the gene frequencies, p × q. Because
we want to know the overall probability of either event, we use
the addition rule, adding the probabilities to obtain a heterozygote
frequency of pq + pq = 2pq. Overall,
the genotype frequencies of a two-allele locus are equal to p2 + 2pq + q2 = 1. This
relationship indicates that the gene frequency (q)
for alleles causing CF is equal to q1/2 or
(1/2500)1/2 or 1/50.
The frequency of normal alleles, p, is (2499/2500)1/2 or
approximately 1. The frequency of heterozygotes (2pq)
is equal to 2(1)(1/50) = 1/25. Thus,
the frequency of heterozygous carriers is approximately 100 times
higher than the frequency of affected individuals.
++
The probabilities of two carriers producing children with two
normal alleles (homozygous normal), a normal allele and a disease-causing allele
(heterozygous carriers), or two disease-causing alleles (homozygous
affected) are 0.25, 0.5, and 0.25, respectively. Thus, on average,
one quarter of the children produced by heterozygous carriers will
be affected with an autosomal-recessive condition. If a child is known
not to be affected, the likelihood that he or she is a carrier is
2:3, ie, likelihood of being a heterozygous carrier (0.5) divided
by the likelihood of being a heterozygous carrier (0.5) plus the
likelihood of being homozygous normal (0.25).
++
An idealized pedigree for autosomal-recessive inheritance (Fig. 170-2) illustrates several important
characteristics: First, autosomal-recessive disorders are usually
observed in one or more siblings but are not usually found in other generations.
Second, similar to autosomal-dominant conditions, males and females
are affected in equal proportions, and males and females are equally
likely to transmit the disease-causing mutation. Third, on average
about 25% of the offspring of two heterozygous carriers
will be affected. Last, consanguinity is observed more often in
pedigrees of autosomal-recessive disorders compared to autosomal-dominant
conditions. Consanguinity refers to the mating
of closely related individuals, who are more likely to share the
identical disease-causing alleles of a locus because of descent
from a common ancestor.
++
++
Genes that are located on the X or Y chromosome are known as
sex-linked genes. The Y chromosome has relatively few genes and
is the smallest of the human chromosomes, about 70 megabases (Mb).
One important gene on the Y chromosome is called the sex-determining
region Y (SRY) gene. Mutations of SRY can
result in individuals with normal external female genitalia and
gonadal dysgenesis (ie, abnormal formation of the gonads). However,
this is an uncommon cause of abnormalities of sexual differentiation
in humans.
++
The X chromosome is more than twice as large as the Y chromosome
(about 160 Mb) and contains about 1000 genes that play a variety
of roles during development and adult life. A number of well-known
pediatric genetic conditions are caused by alterations of X-linked
genes, including hemophilia A, Duchenne and Becker muscular dystrophies,
red–green color blindness, ocular albinism with neurosensory
hearing loss, anhidrotic ectodermal dysplasia, and ornithine transcarbamoylase
deficiency. In addition, loci for more than 60 phenotypes associated
with mental retardation (eg, fragile X syndrome) have been mapped
to the X chromosome, although genes have been cloned for only a
handful of these conditions.
++
Females have two copies and males one copy of the X chromosome.
Yet the quantity of product encoded by most X-linked genes does
not differ between males and females. The equalization of X-linked
gene products is called dosage compensation and
is produced by the inactivation of one of the X chromosomes early
in female embryonic development. This inactivation process is random,
so the maternally and paternally derived X chromosomes will each
be inactive in about half of the embryo’s cells. Once an
X chromosome is inactivated, the same X chromosome remains inactivated
in all descendants of the cell. Thus, all normal females have at
least two populations of cells (somatic mosaicism), one containing
a paternally derived active X chromosome and the other containing
a maternally derived active X chromosome, which becomes clearly
evident if the maternally and paternally derived X chromosomes produce
different products. For example, the retinas of women who are carriers
for X-linked ocular albinism demonstrate alternating patches of
pigmented and nonpigmented cells corresponding respectively to cells
in which the disease-bearing X chromosome (nonpigmented) or the
normal X chromosome (pigmented) has been inactivated.
++
Inactivation of the X chromosome takes place approximately 2
weeks after fertilization, begins in a region of the X chromosome
called the inactivation center, and subsequently
spreads along the chromosome. The X inactivation center contains
at least one gene required for inactivation, XIST. XIST is
transcribed only from the inactive X chromosome, but its mRNA never
leaves the nucleus and is not translated into protein. The mRNA
product of XIST appears to coat the portions of
the X chromosome that are subsequently inactivated. Maintenance
of inactivation appears to depend on methylation of CG dinucleotide
repeats that are commonly found in the 5´ (upstream) regions
of genes. Inactivation of the X chromosome is incomplete, and genes
in several regions continue to be transcribed from the inactivated
X chromosome. Some of these genes have transcribed homologues on
the Y chromosome, and thus dosage compensation is maintained by
their activation on both X chromosomes in females.
++
The inheritance patterns of X-linked conditions differ substantially
from the inheritance patterns of autosomal disorders. Females can
be homozygous for a disease allele at a given locus, heterozygous
for a disease allele and a normal allele, or homozygous for a normal
allele at a locus. Males have only one X chromosome and are considered
hemizygous (hemi-, “half”) for
an allele at a locus on the X chromosome. If a male inherits the
altered allele for a recessive disorder, he will be affected with
the condition because the Y chromosome does not carry a normal allele
that might compensate for the effects of the disease gene. In contrast,
X-linked dominant disorders can cause the disease condition in either
males or females because the presence of only one copy of an altered
allele is sufficient for disease expression.
++
For X-linked recessive disorders, the frequency of the disease
condition in males is equal to the gene frequency q. This
is because all males with the altered gene have the disease condition.
Because females need two copies of the altered allele to manifest
the condition, the frequency of the disease condition is q2.
For example, hemophilia A has a prevalence of approximately 1/10,000
males (q = 0.0001). Thus, affected females
will be observed in q2 (q2 = 0.00000001)
or 1/100,000,000 individuals. Consequently, X-linked recessive
disorders are likely to be found much more frequently in males than
females.
++
A pedigree (Fig. 170-3) illustrates some
of the important characteristics of an X-linked recessive trait.
First, only females are able transmit the disorder to their sons;
in other words, there is no male-to-male transmission for X-linked
recessive conditions. Second, sibships containing only carrier females
(unaffected) appear as “skipped generations.” In
these generations, carrier females appear unaffected, and the X
chromosome transmitted to males by their mother contains a normal
allele. An affected father transmits the disease allele to all his
daughters, who in turn transmit it to half of their sons on average.
++
++
At least three mechanisms account for some female carriers of
X-linked recessive disorders manifesting some of or all the characteristics
of the condition. First, because inactivation of the X chromosome
is a random process within each cell, sometimes a much higher proportion
of X chromosomes bearing a normal allele is inactivated than X chromosomes
carrying a disease allele. These affected carrier females are known
as manifesting heterozygotes. For many disorders, manifesting
heterozygotes have a milder form of the condition compared with
affected males. For example, approximately 5% of women
carrying an allele for hemophilia A have factor VIII levels low
enough to cause a mild form of the disease. Second, some women have
only a single X chromosome (ie, Turner syndrome, see below) and therefore
will manifest X-linked recessive conditions for which they would
otherwise have been carriers. Last, chromosomal aberrations such
as deletions or rearrangements involving the X chromosome and an
autosome can also result in affected females. X chromosome rearrangements
involving the mutation-containing X chromosome cause disease in
females because the normal X chromosome will be preferentially inactivated
to avoid inactivating the autosome attached to the other X chromosome.
These events are relatively rare.
++
Some single-gene conditions are caused by mechanisms that are
transmitted in patterns that are distinct from those of autosomal
and sex-linked conditions. Many of these conditions are relatively
uncommon. Nevertheless, these nontraditional mechanisms of disease
often explain cases that are otherwise inconsistent with the current
state of knowledge of genetic disorders. For example, the expression
of most traits is independent of the parent of origin of the causative
allele. Recently, however, it has become apparent that this is not
always true. One of the most striking examples to date is caused
by a deletion of 2 to 4 Mb of chromosome 15. When this deletion
is inherited from the father, the offspring is born with Prader-Willi
syndrome: severe neonatal hypotonia, obesity, small hands and feet,
and an unusual behavioral profile including mental retardation (Fig. 170-4). In contrast, when the deletion
is inherited from the mother, the offspring manifests Angelman syndrome,
appearing normal at birth but subsequently developing seizures,
mental retardation, ataxia, and a characteristic posture.
++
++
Within the 2 to 4 Mb region of chromosome 15 that is deleted
in patients with either Prader-Willi or Angelman syndrome lie several
genes that are transcriptionally active on one of the chromosomes
inherited from the mother or father but not both (ie, they are active
on only one chromosome). If these genes are deleted, the result
is a complete loss of the encoded product and a disease condition.
If all of the paternally active genes are lost, the offspring has
Prader-Willi syndrome (Fig. 170-5). Angelman
syndrome results from the deletion of a maternally active gene called ubiquitin-protein
ligase E3A (UBE3A) that is involved in
the degradation of proteins within the brain (Fig.
170-5). The differential activation of genes contingent on
whether they are maternally or paternally transmitted is called genomic
imprinting.
++
++
Approximately 70% of cases of Angelman or Prader-Willi
syndrome are caused by chromosome deletions. However, several additional mechanisms
may also cause these disorders. One of these is the inheritance
of both copies of a chromosome, in part or the whole chromosome,
from only one parent, called uniparental disomy. Thus,
if both copies of the maternal chromosome 15 are inherited, the
resulting offspring lacks the paternally active genes and develops
Prader-Willi syndrome. Conversely, uniparental disomy of paternal
chromosome 15 causes Angelman syndrome. Uniparental disomy also
has been found to be responsible for some cases of Beckwith-Wiedemann
syndrome. Uniparental disomy has been reported for most human chromosomes,
although these abnormalities are, overall, uncommon.
++
Other cases that have been difficult to explain until recently
include the expression of autosomal-recessive conditions (eg, cystic
fibrosis) in the offspring of matings between a carrier parent (ie,
heterozygous for a disease allele and a normal allele) and an unaffected parent
homozygous for two normal alleles. Using molecular markers that
can identify specifically each of the four parental chromosomes,
it was found that both copies of the chromosome bearing a disease
allele were identical and inherited from the heterozygous parent
(uniparental isodisomy). The proportion of genetic conditions caused
by this type of abnormality appears to be low.
++
The majority of genetic conditions are caused by abnormalities
of the nuclear genome. Nevertheless, a growing number of conditions are
caused by defects of the only genetic material existing outside
of the nucleus, that of the mitochondria. In contrast to the nuclear
genome, which is diploid (two copies of each gene),
the mitochondrial genome contains only one copy of each gene and
is thus haploid. Because of the unique properties
of mitochondria, these disorders exhibit a characteristic pattern of
inheritance and wide phenotypic variability. Each of the 100 to
100,000 mitochondria within a cell contains at least several copies
of a 16,569-bp genome in the mitochondrial matrix, and each mitochondrial
DNA (mtDNA) molecule is identical. The state in which all copies
of mtDNA are identical is called homoplasmy. The
mtDNA molecule encodes 13 polypeptides that are components of the
oxidative phosphorylation (OXPHOS) system (another approximately
90 components are encoded by the nuclear genome), 2 ribosomal RNAs,
and 22 transfer RNAs. Replication and transcription of mtDNA take
place within the mitochondria and are facilitated by nuclear-encoded
proteins. In humans, mitochondria in the midpiece of the sperm may
enter the egg, but the mtDNA from the sperm rarely, if ever, persists
in the embryo. Thus all the mitochondria of the offspring are descendants
of those located within the cytoplasm of the egg. Consequently,
the inheritance of mtDNA is exclusively maternal.
++
Because there is more than one copy of mtDNA within each mitochondrion,
a new mutation in an mtDNA molecule will result in the emergence
of two different mtDNA populations within a mitochondrion. The state
of having two or more different populations of mtDNA molecules is
called heteroplasmy. As cells divide and the mitochondria
proliferate, the proportion of mutant mtDNA molecules within a cell
and the proportion of cells in a tissue or organ containing mitochondria
with mutant mtDNA molecules will change. Mutant mtDNAs diminish
the efficiency of OXPHOS metabolism and cause cells to die and tissues
and organs to deteriorate prematurely. A threshold of mutant mtDNA
molecules within a mitochondrion (typically 85%) must be
exceeded before a biochemical defect disrupts the normal function
of the OXPHOS system. Thus, the larger the proportion of mutant
mtDNA molecules within a cell or tissue is, the higher will be the
likelihood of expressing a disease phenotype or the greater the
severity of disease.
++
Mitochondrial disorders are commonly classified according to
the type of mutation that causes them or their clinical presentation (Table 170-1). In general, mutations in the mtDNA
molecule are either rearrangements (ie, deletions and duplications)
or point mutations (ie, missense or nonsense mutations). Many mtDNA
disorders present with nonspecific neurologic findings such as coma,
seizures, and ataxia. In the neonatal period, mitochondrial disorders
commonly present with metabolic encephalopathy, cardiac or hepatic
failure, and/or lactic acidemia. Although uncommon, mitochondrial
disorders account for a substantial percentage of cerebrovascular accidents
in children. Most mitochondrial disorders are uncommon, but mtDNA
mutations also contribute to common disorders such as deafness and
diabetes mellitus. Mitochondrial mutations have also been implicated
in the process of aging. However, whether these mutations are a
cause or a consequence of the aging process is unclear.
++
++
The identification and characterization of a disease gene are
the first steps in understanding the molecular pathogenesis of a
condition. Further insight is often gained by understanding the
mechanism by which mutations disturb the function of a cell. Most
mutations result in either a gain of function or loss of function
of the encoded product.
++
A disease allele occasionally results in a protein product with
a novel function compared to the normal product. More commonly a
disease allele causes the overexpression of its product or expression
of its product at an inappropriate time or place. These types of
mutations are known as gain-of-function mutations and commonly result
in conditions transmitted in a dominant pattern. Huntington disease,
a late-onset condition characterized by progressive neurologic deterioration,
is caused, in part, by a gain-of-function mutation.
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Some gain-of-function mutations extend the normal function of
a gene. For example, mutations in fibroblast growth factor 3, FGFR3, result
in the uncontrolled activation of the receptor leading to enhanced
inhibition of the growth of long bones (eg, the femur). Depending
on the location of the mutation, this produces hypochondroplasia,
achondroplasia, or thanatophoric dysplasia.
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Some mutations result in the loss of 50% of the encoded
product, and 50% of the product remains available (encoded
by the normal allele). Often, but not exclusively, these loss-of-function
mutations are observed in recessive conditions (eg, galactosemia,
Hurler syndrome). Since carriers for most recessive disorders are
asymptomatic, the availability of 50% of the encoded product
is often enough to prevent disease. In circumstances in which 50% of
the encoded product is not sufficient to prevent disease (haploinsufficiency),
a loss-of-function mutation can also result in dominant disorders.
For example, a deletion of the gene encoding the extracellular matrix
protein, elastin, results in diminished incorporation of elastin
into the wall of large arteries, producing supravalvular aortic
stenosis.
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Another type of loss-of-function mutation results when the encoded
product is not only nonfunctional, but also interferes with the
activity of the normal product and is known as dominant
negative mutation. This type of mutation is usually observed
in genes that encode proteins that are components of multimeric
(containing two or more protein subunits) proteins. For example,
mutations in one of the collagen genes (COL1A1)
can impair the binding of collagen subunits into a normal trimeric
complex, resulting in osteogenesis imperfecta.
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Over the last decade a novel type of mutation produced by an
expansion of a repeated nucleotide motif has been found to cause
a variety of genetic conditions. Most commonly, these disorders
are associated with an expansion of a trinucleotide repeat (eg,
CAG, CTG). These repeats can be located within a gene or in the
5′ or 3′ untranslated
portions of a gene. One of the most notable of the genetic conditions
caused by an expansion of a trinucleotide repeat is fragile X syndrome,
the most common cause of inherited mental retardation in males.
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Fragile X syndrome is an X-linked condition with 80% penetrance
in males and 30% penetrance in females. It is caused by
the expansion of a CGG repeat in the 5′ untranslated
region of a gene called FMR1. In unaffected men,
there are typically 6 to 50 CGG repeats. Males who carry the disease
allele but do not have fragile X syndrome are called transmitting
males. An intermediate number of repeats (ie, 50–230),
or premutation, is found in transmitting males
and their female offspring. When these female offspring transmit
the gene to their offspring, the premutation expands to a full mutation ranging
up to several thousand repeats. Men with full mutations have no FMR1 mRNA
in their cells, indicating that transcription of FMR1 has
been silenced. Furthermore, premutations tend to become larger in
successive generations, and larger premutations are more prone to
expansion to a full mutation. These expansions do not occur when
a male transmits the premutation. This explains why males with a
premutation cannot transmit the disease to their daughters and why
grandsons and great-grandsons of normal transmitting males are more
likely to be affected with fragile X syndrome.
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Expansions of trinucleotide repeats are also associated with
various progressive neurodegenerative disorders, including some
of the spinocerebellar ataxias, Huntington disease, and myotonic
dystrophy. As discussed previously, some of these trinucleotide
repeat expansions are also associated with anticipation. The expansion
of a 12-bp repeat from 2 or 3 repeats to approximately 60 repeats
has been discovered to cause autosomal-recessive myoclonic epilepsy.
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The prevalence of many genetic disorders varies extensively among
human populations. For example, the prevalence of cystic fibrosis
varies from 1/313 in the Hutterites of Alberta, Canada,
to 1/90,000 in Asians, a difference of nearly 300-fold.
Although mutation is ultimately the source of all variation in the
genome, different mutation rates among populations are not a sufficient
explanation for wide variation in prevalence rates of genetic conditions.
Varied prevalence rates are the imprints left by evolutionary forces
other than mutation (ie, natural selection, genetic drift, gene flow)
on disease-related variation in human populations. Explaining these
patterns of disease-related genetic variation facilitates understanding
the etiology and pathogenesis of genetic conditions. However, estimating
disease-related genetic variation depends on understanding the distribution
of total genetic variation. Over the past decade a variety of new
molecular and statistical tools for estimating genetic variation
have been applied widely to human populations to further explain
the genetic bases of various medical conditions and traits. Further,
these tools have provided new insights about how evolutionary forces have
shaped disease-related genetic variation in contemporary populations.
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Genetic drift refers to the random fluctuations
in gene frequencies that occur from generation to generation as
the result of sampling a limited number of gametes. As the size
of the population decreases, the degree of fluctuation increases.
Genes that are rare in large populations may be common in small populations
or vice versa. Genetic drift can be caused by a substantial reduction
in the size of a population (a population bottleneck) or
the separation of a subset of a larger population (founder
effect). For example, according to well-maintained historical
records, the Old Order Amish in Lancaster County, Pennsylvania,
were established by approximately 50 couples. Nearly half of all
the reported cases of Ellis-van Creveld (EVC) syndrome (an autosomal-recessive
skeletal dysplasia characterized by short stature, polydactyly, and
cardiac defects caused by mutations in EVC) have been identified
in the Amish population. The relatively small founding population
of the Amish and their custom of marrying only within their relatively
isolated community (endogamy) have resulted in
a very high carrier frequency of the disease-causing alleles of
EVC.
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Natural selection alters the frequency of a trait (disease
condition) contingent on the relative fitness of a phenotype
in a given environmental context. Phenotypes with a high fitness are
positively selected, and phenotypes with a low fitness are negatively
selected. Traditionally, fitness has been estimated by the number of
descendants produced by those who possess a given genotype or phenotype.
For example, individuals who die without descendants have a fitness
of zero, whereas individuals with higher numbers of offspring have
higher fitness values. Diseases maintained in a population by natural
selection illustrate the relationship among genes, phenotypes, and
the environment. Consanguinity is defined as the mating
of related individuals. Although consanguinity is relatively rare
in Western populations, it is common in many populations of the
world. Consanguinity increases the chances that a mating couple
will both carry the same disease allele. Thus, consanguineous matings
are more likely to produce offspring affected with autosomal-recessive
disorders.
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Many studies have shown that mortality rates among the offspring
of first-cousin marriages are substantially higher than in the general
population. Furthermore, the prevalence of genetic disease is approximately
twice as high among the offspring of first-cousin marriages. There
are few data about the mating of first-degree relatives (ie, incestuous
matings), although the prevalence of mental retardation, short stature,
and major congenital anomalies is clearly higher.