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.
A pedigree illustrating an autosomal-dominant disorder.
Affected individuals are represented by pink shading. By convention,
males are shown as squares and females are shown as circles. Note
the male-to-male transmission and that no generation is skipped.
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.
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.
A pedigree illustrating the inheritance pattern of an
autosomal recessive disorder. Affected individuals are represented by
pink shading and heterozygotes by partial pink shading.
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
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
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.
A pedigree showing the inheritance of an X-linked recessive
condition. Pink-shaded symbols represent affected individuals, and
dotted symbols represent heterozygous carriers. Only females can
transmit the disorder to their sons. Fathers transmit trait to all
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.