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FACTORS THAT MAY COMPLICATE INHERITANCE PATTERNS

The inheritance patterns described previously for postaxial polydactyly and albinism are quite
straightforward. However, many autosomal diseases display more complex patterns. Some of
these complexities are described next.

New Mutation
If a child has been born with a genetic disease and there is no history of the disease in the
family, it is possible that the disease is the product of a new mutation (this is especially likely
if the disease in question is autosomal dominant). That is, the gene transmitted by one of the
parents underwent a change in DNA resulting in a mutation from a normal to a disease-
causing allele. The genes at this locus in the parent's other germ cells would still be normal. In
this case the recurrence risk for the parents' subsequent offspring would not be elevated
above that of the general population. However, the offspring of the affected child may have a
substantially elevated occurrence risk (e.g., it would be 50% for an autosomal dominant
disease). A large proportion of the observed cases of many autosomal dominant diseases are
the result of new mutations. For example, it is estimated that 7/8 of all cases of
achondroplasia are caused by new mutations, while only 1/8 are transmitted by
achondroplastic parents. This is primarily because the disease tends to limit the potential for
reproduction. In order to provide accurate risk estimates, it is essential to know whether an
observed case is due to an inherited disease gene or a new mutation. This can be done only
if an adequate family history has been taken.
▪ New mutations are a frequent cause of the appearance of a genetic
disease in an individual with no previous family history of the
disorder. The recurrence risk for the individual's siblings is very low,
but it may be substantially elevated for the individual's offspring.

Germline Mosaicism
Occasionally, two or more offspring may present with an autosomal dominant or X-linked
disease when there is no family history of the disease. Since mutation is a rare event, it is
unlikely that this situation would be due to multiple mutations in the same family. The
mechanism most likely to be responsible is termed germline mosaicism (mosaicism
describes the presence of more than one genetically distinct cell line in the body). During the
embryonic development of one of the parents, a mutation occurred that affected all or part of
the germ line but few or none of the somatic cells of the embryo (Fig. 4-12). Thus, the parent
carries the mutation in his or her germ line but does not actually express the disease because
the mutation is absent in other cells of the body. As a result, the parent can transmit the
mutation to multiple offspring. Although this phenomenon is relatively rare, it can have
significant effects on recurrence risks when it does occur.
Figure 4.12 A mutation occurs in one cell of the developing embryo. All descendants of that cell have the same
mutation, resulting in mosaicism. If the first mutated cell is part of the germline lineage, then germline mosaicism
results.

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Germline mosaicism has been studied extensively in the lethal perinatal form of osteogenesis
imperfecta (OI type II; see Chapter 2), which is caused by mutations in the type 1 procollagen
genes. The fact that unaffected parents sometimes produced multiple offspring affected with
this disease led to the conclusion that type II OI was an autosomal recessive trait. This was
disputed by studies in which the polymerase chain reaction (PCR) technique was used to
amplify DNA from the sperm of a father of two children with type II OI. This DNA was
compared with DNA extracted from his somatic cells (skin fibroblasts). Although procollagen
mutations were not detected in the fibroblast DNA, they were found in approximately 1 of
every 8 sperm cells. This was a direct demonstration of germline mosaicism in this individual.
Although germline mosaicism has thus been demonstrated for type II OI, most non-inherited
cases (approximately 95%) are thought to be caused by isolated new mutations, and a few
cases of true autosomal recessive inheritance have also been documented.

Other diseases in which germline mosaicism has been observed include achondroplasia,
neurofibromatosis type 1, Duchenne muscular dystrophy, and hemophilia A. Germline
mosaicism is relatively more common in the latter two diseases, both of which are discussed
further in Chapter 5. It has been estimated that germline mosaicism accounts for up to 15% of
Duchenne muscular dystrophy cases and 20% of hemophilia A cases in which there is no
previous family history.
▪ Germline mosaicism occurs when all or part of a parent's germ line
is affected by a disease mutation but the somatic cells are not. It
elevates the recurrence risk for future offspring of the mosaic parent.

Variable Expression
A similar complication is variable expression. Here, the penetrance may be complete, but
the severity of the disease can vary greatly. A well-studied example of variable expression in
an autosomal dominant disease is neurofibromatosis type 1, or von Recklinghausen disease
(after the German physician who described the disorder in 1882). Clinical Commentary 4-4
provides further discussion of this disorder. A parent with mild expression of the disease-so
mild that he or she is not aware of it-can transmit the gene to a child, who may have severe
expression. As with reduced penetrance, variable expression provides a mechanism for
disease genes to survive at higher frequencies in populations. www

It should be emphasized that penetrance and expression are distinct entities. Penetrance is
an all-or-none phenomenon: one either has the disease phenotype or does not. Variable
expression refers to the extent of expression of the disease phenotype.

The causes of variable expression usually are not known. Environmental effects can
sometimes be responsible: in the absence of a certain environmental factor, the gene is
expressed with diminished severity or not at all. Another possible cause is the interaction of
other genes, called modifier genes, with the disease gene. An example of a human modifier
gene is a locus on chromosome 19 that appears to influence whether meconium ileus
develops in individuals with cystic fibrosis (see Clinical Commentary 4-1). Finally, as the
molecular basis of mutation becomes better understood, it is clear that some cases of
variable expression are caused by different types of mutations (i.e., different alleles) at the
same disease locus. This is termed allelic heterogeneity. In some cases, clinically distinct
diseases may be the result of allelic heterogeneity, as in the β-globin mutations that can
cause either sickle cell disease or various β-thalassemias.

Osteogenesis imperfecta is one disease in which genetic studies have helped to explain
variable expression. Mutations that affect amino acids near the carboxyl terminal of the
procollagen molecule generally cause more severe consequences than do mutations affecting
the molecule near its amino terminal. It is also well documented that affected members of the
same family, having the same mutation, can nevertheless manifest large differences in
disease severity. This may be a consequence of different genetic "backgrounds" (i.e., modifier
genes) in related individuals. And nongenetic events, such as an accidental bone fracture,
can influence the severity of the disorder. Once a fracture occurs, casting and immobilization
lead to a loss of bone mass, which further predisposes the patient to future fractures. Thus, a
chance environmental event (e.g., trauma leading to a fracture in a baby during delivery) can
cause a significant increase in severity of expression. Osteogenesis imperfecta thus provides
examples of each factor thought to influence variable expression: environmental events,
modifier genes, and allelic heterogeneity.
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CLINICAL COMMENTARY 4.3
CLINICAL COMMENTARY 4.3
Huntington Disease
Huntington disease (HD) affects approximately 1 in 20,000 persons of European
descent. It is substantially less common among Japanese and Africans. The disorder
usually presents between the ages of 30 and 50 years, although it has been
observed as early as 2 years of age and as late as 80 years of age.
HD is characterized by a progressive loss of motor control and by psychiatric
problems, including dementia and affective disorder. There is a substantial loss of
neurons in the brain, detectable by imaging techniques such as magnetic resonance
imaging (MRI). Decreased glucose uptake in the brain, an early sign of the disorder,
can be demonstrated by positron-emission tomography (PET). Although many parts
of the brain are affected, the area most noticeably damaged is the corpus striatum. In
some patients the disease leads to a loss of 25% or more of total brain weight (Fig.
4-16).
The clinical course of HD is protracted. Typically, the interval from initial diagnosis to
death is approximately 15 years. As in many neurological disorders, patients with HD
experience difficulties in swallowing; aspiration pneumonia is the most common
cause of death. Cardiorespiratory failure and subdural hematoma (due to head
trauma) are other frequent causes of death. The suicide rate among HD patients is
several times higher than that in the general population. Treatment includes the use
of drugs such as benzodiazepines to help control the choreic movements. Affective
disturbances, which are seen in nearly half of the patients, are sometimes controlled
with antipsychotic drugs and tricyclic antidepressants. Although these drugs help to
control some of the symptoms of HD, there is currently no way to alter the outcome
of the disease.
HD is notable in that affected homozygotes appear to display exactly the same
clinical course as heterozygotes (in contrast to most dominant disorders, in which
homozygotes are more severely affected). This attribute, and the fact that mouse
models in which one copy of the gene is inactivated are perfectly normal, support the
hypothesis that the mutation causes a gain of function (see Chapter 3). In more than
95% of cases, the mutation is inherited from an affected parent. HD has the
distinction of being the first genetic disease mapped to a specific chromosome using
an RFLP marker. James Gusella and colleagues mapped the disease gene to a
region on the distal short arm of chromosome 4 in 1983.
After 10 years of work by a large number of investigators, the disease gene was
cloned. DNA sequence analysis showed that the mutation is a CAG expanded
repeat (see Chapter 3) located within the coding portion of the gene. The normal
repeat number ranges from 10 to 26. Individuals with 27 to 35 repeats are unaffected
but are more likely to transmit a still larger number of repeats to their offspring. The
inheritance of 36 or more copies of the repeat can produce disease, although
incomplete penetrance of the disease phenotype is seen in those who have 36 to 41
repeats. As in many disorders caused by trinucleotide repeat expansion, a larger
number of repeats is correlated with earlier age of onset of the disorder. Also, there
is a tendency for greater repeat expansion when the father, rather than the mother,
transmits the disease gene. This helps to explain the difference in ages of onset for
maternally and paternally transmitted disease seen in Fig. 4-15. In particular, 80% of
cases with onset before 20 years of age (termed "juvenile Huntington disease") are
paternally transmitted, and these cases are accompanied by especially large repeat
expansions. It remains to be seen why the degree of repeat instability in the HD
gene is greater in paternal transmission than in maternal transmission.
Cloning of the HD gene led quickly to the identification of the gene product, huntingtin.
This protein is involved in the transport of vesicles in cellular secretory pathways. In
addition, there is evidence that huntingtin is necessary for the normal production of brain-
derived neurotrophic factor. The CAG repeat expansion produces a lengthened series of
glutamine residues near huntingtin's amino terminal. Although the precise role of the
expanded glutamine tract in disease causation is unclear, recent studies show that it
leads to a buildup of toxic protein aggregates within and near neuronal nuclei. This
buildup is associated with the early neuronal death that is characteristic of HD.

Figure 4.16 Cross section of the brain of an adult with Huntington disease, illustrating marked striatal atrophy. (Courtesy
Dr. Jeanette Townsend, University of Utah Health Sciences Center.)

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CLINICAL COMMENTARY 4.4
Neurofibromatosis: A Disease with Highly Variable Expression
Neurofibromatosis type 1 (NF1) (Fig. 4-17) is one of the most common autosomal
dominant disorders, affecting approximately 1 in 3,000 individuals. It offers a good
example of variable expression in a genetic disease. Some patients have only a few
café-au-lait spots (from the French for "coffee with milk," describing the color of the
hyperpigmented skin patches), Lisch nodules (benign growths on the iris), and perhaps
neurofibromas (nonmalignant peripheral nerve tumors). These individuals are often
unaware that they have the condition. Other patients have a much more severe
expression of the disorder, including hundreds to thousands of neurofibromas, optic
gliomas (benign tumors of the optic nerve), learning disabilities, hypertension, scoliosis
(lateral curvature of the spine), and malignancies (e.g., malignant peripheral nerve
sheath tumors, which can arise from plexiform neurofibromas). Fortunately, about two
thirds of patients have only a mild cutaneous involvement. Fewer than 10% develop
malignancies as a result of the disorder. Expression can vary significantly within the
same family: a mildly affected parent can produce a severely affected offspring.
Figure 4.17 Neurofibromatosis type 1 (NF1). A, A young adult with multiple dermal neurofibromas of the trunk. A café-
au-lait spot can be seen in the right upper abdomen. B, In a second patient with NF1, a large plexiform neurofibroma
hangs from the lower right back, causing considerable inconvenience and discomfort. (The term plexiform is from the
Latin plexus = "braid," describing the complex, tangled structure of these tumors). The tumor was surgically removed.
Approximately 25% of NF1 patients develop plexiform neurofibromas. (B, Courtesy Dr. David Viskochil, University of
Utah Health Sciences Center.)

A standard set of diagnostic criteria for NF1 has been developed. Two or
more of the following must be present:

1. Six or more café-au-lait spots greater than 5 mm in diameter in
prepubertal subjects and greater than 15 mm in postpubertal
subjects
2. Freckling in the armpits or groin area
3. Two or more neurofibromas of any type or one plexiform
neurofibroma (i.e., an extensive growth that occurs along a large
nerve sheath)
4. Two or more Lisch nodules
5. Optic glioma
6. Distinctive bone lesions, particularly an abnormally formed
sphenoid bone or tibial pseudarthrosis*

7. A first-degree relative diagnosed with neurofibromatosis using the
previous six criteria

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Although NF1 has highly variable expression, the penetrance of this gene
is virtually 100%. It has one of the highest known mutation rates, about 1
in 10,000 per generation. Approximately 50% of NF1 cases are the result
of new mutations. In 1987 the gene was mapped to chromosome 17q by
researchers in Salt Lake City, and it was isolated and cloned 3 years later.
It is a large gene, spanning approximately 350 kb of DNA. Its large size,
which presents a sizable "target" for mutation, may help to account for the
high mutation rate. The gene encodes a 13-kb mRNA transcript, and the
gene product, termed neurofibromin, acts as a tumor suppressor (see
Chapter 11).
A mutation in the NF1 gene that occurs during embryonic development will
affect only some cells of the individual, resulting in somatic mosaicism. In
this case, the disease features may be confined to only one part of the
body (segmental neurofibromatosis).
Neurofibromatosis type 2 (NF2) is much rarer than NF1 and involves café-
au-lait spots and bilateral acoustic neuromas (tumors affecting the eighth
cranial nerve). It does not, however, involve true neurofibromas. The term
"neurofibromatosis type 2" is thus a misnomer. The NF2 gene, which was
mapped to chromosome 22, encodes a tumor suppressor protein called
merlin or schwannomin.
Mild cases of neurofibromatosis may involve very little clinical
management. However, surgery may be required if malignancies develop
or if benign tumors interfere with normal function. Scoliosis, tibial
pseudarthrosis, and/or tibial bowing, seen in fewer than 5% of cases, may
require orthopedic management. Hypertension may develop and is often
secondary to a pheochromocytoma or a stenosis (narrowing) of the renal
artery. The most common clinical problems in children are learning
disabilities (seen in about 50% of individuals with NF1), short stature, and
optic gliomas (which can lead to vision loss). Close follow-up can help to
detect these problems and minimize their effects.
▪ Variable expression of a genetic disease may be caused by
environmental effects, modifier genes, or allelic heterogeneity.

Reduced Penetrance
Figure 4.13 Pedigree illustrating the inheritance pattern of retinoblastoma, a disorder with reduced penetrance. The
unaffected obligate carrier is lightly shaded, and affected individuals are heavily shaded.

Another important characteristic of many genetic diseases is reduced penetrance: an
individual who has the genotype for a disease may not exhibit the disease phenotype at all,
even though he or she can transmit the disease gene to the next generation. Retinoblastoma,
a malignant eye tumor (Clinical Commentary 4-2), is a good example of an autosomal
dominant disorder in which reduced penetrance is seen. The transmission pattern of this
disorder is illustrated in Fig. 4-13. Family studies have shown that about 10% of the obligate
carriers of the retinoblastoma susceptibility gene (i.e., those who have an affected parent and
affected children and therefore must themselves carry the gene) do not have the disease. The
penetrance of the gene is then said to be 90%. Penetrance rates are usually estimated by
examining a large number of families and determining what proportion of the obligate carriers
(or obligate homozygotes, in the case of recessive disorders) develop the disease phenotype.
www
▪ Reduced penetrance describes the situation in which individuals who
have a disease-causing genotype do not develop the disease
phenotype.

Anticipation and Repeat Expansion
Since the early part of the 20th century, it has been observed that some genetic diseases
seem to display an earlier age of onset and/or more severe expression in the more recent
generations of a pedigree. This pattern is termed anticipation, and it has been the subject of
considerable controversy and speculation. Many researchers believed that it was an artifact of
better observation and clinical diagnosis in more recent times: a disorder that previously may
have remained undiagnosed until age 60 years might now be diagnosed at age 40 simply
because of better diagnostic tools. Others, however, believed that anticipation could be a real
biological phenomenon, although evidence for the actual mechanism remained elusive.

Figure 4.21 A three-generation family affected with myotonic dystrophy. The degree of severity increases in each
generation. The grandmother (right) is only slightly affected, but the mother (left) has a characteristic narrow face and
somewhat limited facial expression. The baby is more severely affected and has the facial features of children with
neonatal-onset myotonic dystrophy, including an open, triangle-shaped mouth. The infant has more than 1,000
copies of the trinucleotide repeat, whereas the mother and grandmother each have approximately 100 repeats.

Recently, molecular genetics has provided good evidence that anticipation does in fact have a
biological basis. This evidence has come, in part, from studies of myotonic dystrophy, an
autosomal dominant disease that involves progressive muscle deterioration (Fig. 4-21). Seen
in approximately 1 in 8,000 individuals, myotonic dystrophy is the most common muscular
dystrophy that affects adults. In addition to affecting skeletal muscles, this disorder produces
cardiac arrhythmias (abnormal heart rhythms), testicular atrophy, and cataracts. The disease-
causing gene, which has been mapped to chromosome 19 and subsequently cloned,
encodes a protein kinase. www
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Analysis of the gene has produced some interesting results. The disease mutation is an
expanded CTG trinucleotide repeat (see Chapter 3) that lies in the 3' untranslated portion of
the gene (i.e., a region transcribed into mRNA but not translated into protein). The number of
these repeats is strongly correlated with severity of the disease. Unaffected individuals
typically have 5 to 30 copies of the repeat. Those with 50 to 100 copies may be mildly
affected or have no symptoms. Those with full-blown myotonic dystrophy have anywhere from
100 to several thousand copies of the repeat sequence. The number of repeats often
increases with succeeding generations: a mildly affected parent with 80 repeats may produce
a severely affected offspring who has more than 1,000 repeats (Fig. 4-22). Many families
have now been documented in which the number of repeats increases through successive
generations, accompanied by increasing severity of the disorder. There is thus strong
evidence that expansion of this trinucleotide repeat is the cause of anticipation in myotonic
dystrophy.
Figure 4.22 A, Myotonic dystrophy pedigree illustrating anticipation. In this case, the age of onset for family members
affected with an autosomal dominant disease is lower in more recent generations. B, An autoradiogram from a Southern
blot analysis of the myotonic dystrophy gene in three individuals. Individual A is homozygous for a 4- to 5-repeat allele and
is normal. Individual B has one normal allele and one disease allele of 175 repeats; this individual has myotonic
dystrophy. Individual C is also affected with myotonic dystrophy and has one normal allele and a disease-causing allele of
approximately 900 repeats. (B, Courtesy Dr. Kenneth Ward and Dr. Elaine Lyon, University of Utah Health Sciences
Center.)

How does a mutation in the 3' untranslated portion of the gene produce the many disease
features of myotonic dystrophy? Mouse models of this disease indicate that the expanded
repeat decreases production of the protein product (a protein kinase), which results in cardiac
conduction defects that produce arrhythmias. In addition, the mutation alters the mRNA
transcript such that it remains in the nucleus and interacts with RNA-binding proteins to block
their normal activity. This produces myotonic myopathy. Finally, the mutation may interfere (by
altering chromatin structure) with a downstream transcription-factor gene, SIX5, resulting in
cataract formation. Thus, analysis of the disease-causing mutation and its effect on nearby
genes helps to explain the pleiotropy observed in myotonic dystrophy.
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Table 4-3. Disease Associated with Repeat Expansions
Disease Description Repeat Normal Parent in Location
sequence range, whom of
abnormal expansion expansion
range usually
occurs
Category 1
Huntington disease Loss of motor CAG 6-34; 36-100 More often Exon
control, or more through father
dementia,
affective disorder
Spinal and bulbar muscular Adult-onset CAG 11-34; 40-62 More often Exon
atrophy motor-neuron through father
disease
associated with
androgen
insensitivity
Spinocerebellar ataxia type 1 Progressive CAG 6-39; 41-81 More often Exon
ataxia, through father
dysarthria,
dysmetria
Spinocerebellar ataxia type 2 Progressive CAG 15-29; 35-59 - Exon
ataxia, dysarthria
Spinocerebellar ataxia type 3 Dystonia, distal CAG 13-36; 68-79 More often Exon
(Machado-Joseph disease) muscular through father
atrophy, ataxia,
external
ophthalmoplegia
Spinocerebellar ataxia type 6 Progressive CAG 4-16; 21-27 - Exon
ataxia,
dysarthria,
nystagmus
Spinocerebellar ataxia type 7 Progressive CAG 7-35; 38-200 More often -
ataxia, through father
dysarthria, retinal
degeneration
Spinocerebellar ataxia type 17 Progressive CAG 29-42; 47-55 - Exon
ataxia, dementia,
bradykinesia,
dysmetria
Dentatorubral-pallidoluysian Cerebellar CAG 7-25; 49-88 More often Exon
atrophy/Haw River syndrome atrophy, ataxia, through father
myoclonic
epilepsy,
choreoathetosis,
dementia
Category 2
Pseudoachondroplasia/multiple Short stature, GAC 5; 6-7 - Exon
epiphyseall dysplasia joint laxity,
degenerative
joint disease
Oculopharyngeal muscular Proximal limb GCG 6; 7-13 - Exon
dystrophy weakness,
dysphagia,
ptosis
Cleidocranial dysplasia Short stature, GCG, GCT, 17; 27 - Exon
open skull GCA (expansion
sutures with observed in
bulging calvaria, one family)
clavicular
hypoplasia,
shortened
fingers, dental
anomalies
Synpolydactyly Polydactyly and GCG, GCT, 15; 22-25 - Exon
syndactyly GCA
Category 3
Myotonic dystrophy (DM1; Muscle loss, CTG 5-37; 100 to Either parent, 3'
chromosome 19) cardiac several but expansion untranslated
arrhythmia, thousand to congenital region
cataracts, frontal form through
balding mother
Myotonic dystrophy (DM2; Muscle loss, CCTG <75; 75- - 3'
chromosome 3) cardiac 11,000 untranslated
arrhythmia, region
cataracts, frontal
balding
Friedreich ataxia Progressive limb GAA 7-22; 200- Disorder is Intron
ataxia, 900 or more autosomal
dysarthria, recessive, so
hypertrophic disease
cardiomyopathy, alleles are
pyramidal inherited from
weakness in legs both parents
Fragile X syndrome (FRAXA) Mental CGG 6-52; 200- Exclusively 5'
retardation, large 2000 or through untranslated
ears and jaws, more mother region
macroorchidism
in males
Fragile site (FRAXE) Mild mental GCC 6-35; >200 More often 5'
retardation through untranslated
mother region
Spinocerebellar ataxia type 8 Adult-onset CTG 16-37; 107- More often 3'
ataxia, 127 through untranslated
dysarthria, mother region
nystagmus
Spinocerebellar ataxia type 10 Ataxia and ATTCT 12-16; 800- More often Intron
seizures 4500 through father
Spinocerebellar ataxia type 12 Ataxia, eye CAG 7-28; 66-78 - 5'
movement untranslated
disorders; region
variable age at
onset
Progressive myoclonic epilepsy Juvenile-onset 12-bp repeat 2-3; 30-75 Autosomal 5'
type 1 convulsions, motif recessive untranslated
myoclonus, inheritance so region
dementia transmitted by
both parents

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Recently, a locus on chromosome 3 was discovered in which a 4-bp (CCTG) expanded repeat
can also cause myotonic dystrophy. Again, the repeat is located in the 3' untranslated region
of the gene. The phenotype associated with the chromosome 3 mutation is highly similar to
that of the chromosome 19 mutation, although it sometimes is less severe. Myotonic
dystrophy thus illustrates several important genetic principles: anticipation, pleiotropy, and
locus heterogeneity.

As discussed in Clinical Commentary 4-3, trinucleotide repeat expansion is also associated
with anticipation in Huntington disease. It has also been observed in the fragile X syndrome, a
leading genetic cause of mental retardation to be discussed in Chapter 5. Repeat expansions
have now been identified as a cause of more than 20 genetic diseases (Table 4-3), and
anticipation is observed in most of these diseases.

As more repeat expansion diseases have been identified, some general patterns have begun
to emerge. These diseases can be grouped into three categories, as indicated in Table 4-3.
The first category consists of neurological diseases, such as Huntington disease and most of
the spinocerebellar ataxias, that are caused by a CAG repeat expansion in a protein-coding
portion of the gene. The repeats generally expand in number from a normal range of 10 to 35
to a disease-causing range of approximately 50 to 100. Expansions tend to be larger when
transmitted through the father than through the mother, and the mutations have a gain-of-
function effect. The second group consists of phenotypically more diverse diseases in which
the expansions are again small in magnitude and are found in exons. The repeat sequence is
heterogeneous, however, and anticipation is not a typical feature. The third category includes
fragile X syndrome, myotonic dystrophy, two of the spinocerebellar ataxias, juvenile myoclonic
epilepsy, and Friedreich ataxia. The repeat expansions are typically much larger than in the
first two categories: the normal range is generally 5 to 50 trinucleotides, but the disease-
causing range can vary from 200 to several thousand trinucleotides. The repeats are located
outside the protein-coding regions of the gene in all of these disorders, and the mutations
usually have a loss-of-function effect. Repeat expansions are often larger when they are
transmitted through the mother. Anticipation is seen in most of the diseases in categories 1
and 3.
▪ Anticipation refers to progressively earlier or more severe expression of a
disease in more recent times. Expansion of DNA repeats has been shown
to cause anticipation in some genetic diseases. These diseases can be
divided into three major categories, depending on the size of the
expansion, the location of the repeat, the phenotypic consequences of the
expansion, the effect of the mutation, and the parent in whom large
expansions typically occur.