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4.1 Terminology
A location on a chromosome or DNA
molecule, including a gene’s location on a
One of the different forms that a gene
may have in a population.
A1 and A2 are locus A’s alleles, B1 and B2 are locus
B’s alleles, and C1 and C2 are locus C’s alleles.
This is the genetic constitution of an
individual and is also used to refer to the
alleles present at one locus, such as A1A2.
This is the observed biochemical,
physiological, or morphological
characteristics of an individual that are
determined by the genotype and the
environment in which it is expressed.
This is an individual or genotype with
identical alleles at a given locus on a pair
of homologous chromosomes, such as
A1A1 and A2A2.
This is an individual or genotype with
two different alleles at a given locus on a
pair of homologous chromosomes, such
as A1A2.
A trait that is expressed in the same
way in the heterozygote as in the
A trait that is expressed only in the
homozygote. The recessive allele is
masked by a dominant allele when the
two occur together in a heterozygote.
Pedigree charts
The pedigree is one of the most
commonly used tools in medical genetics.
It illustrates the relationships among
family members, and it shows which
family members are affected with a
genetic disease and which members are
To simplify recording the family
history, we make use of schematic
Symbols and configuration of pedigree charts.
Proband: the first individual diagnosed in
the pedigree.
4.2 Single-gene inheritance
Single-gene inheritance are also
known as Mendelian inheritance.
4.2.1 Autosomal dominant (AD)
AA, Aa —affected.
A — mutant gene on autosome.
A pedigree demonstrating the pattern of the
autosomal dominant inheritance.
Characteristics of autosomal
dominant inheritance:
·Usually, males and females are
equally likely to be affected.
·There is no skipping of generations: if
an individual has the disease, one parent
must also have it.
This leads to a vertical transmission
pattern, in which the disease phenotype
is usually seen in one generation after
another. Also, if neither parent has the
disease, none of the children has it.
·Father-son transmission of the disease
gene is observed.
Although father-son transmission is
not required to establish autosomal
dominant inheritance, its presence in a
pedigree excludes certain other modes of
inheritance (particularly X-linked
·Affected family members usually have
unaffected partners and produce a 1:1
ratio of normal and affected children.
Individually, each autosomal dominant
disease is rather rare in populations.
Matings between two individuals both
affected by the same autosomal
dominant disease are thus uncommon.
Most often, affected offspring are
produced by the union of a normal
parent with an affected heterozygote.
The affected parent can pass either a
disease gene or a normal gene to his or
her children. Each event has a
probability of 0.5. Thus on the average,
half of the children will be heterozygotes
and will express the disease, and half
will not.
Figure illustrating the mating of an unaffected
individual (aa) with an individual who is
heterozygous for an autosomal dominant disease
gene (Aa). The genotypes of affected offspring are
Autosomal dominant inheritance is
characterized by vertical transmission of
the disease phenotype, a lack of skipped
generations, and roughly equal numbers
of affected males and females. Father-son
transmission may be observed.
For example: Postaxial polydactyly.
Postaxial polydactyly, the presence of an
extra digit next to the fifth digit.
A pedigree illustrating the inheritance pattern of
postaxial polydactyly, an autosomal dominant
Another example: Achondroplasia.
Mutation of the FGFR3 (fibroblast
growth factor receptor 3) encoded on
chromosome 4 causes decreased growth
of cartilaginous bone, and membranous
bone is unaffected. Symptoms include
large head, prominent forehead, short
limbs, normal trunk size, and lumbar
Reduced stature. Note also the prominent
forehead and low nasal root.
Recurrence Risks.
Parents at risk for producing children
with a genetic disease are often
concerned with the question: What is the
chance that our future children will have
this disease? When one or more children
have already been born with a genetic
disease, the parents are given a
recurrence risk. This is the probability
that subsequent children will also have
the disease. If the parents have not yet
had children but are known to be at risk
for having children with a genetic
disease, an occurrence risk can be given.
When one parent is affected by an
autosomal dominant disease
(heterozygote) and the other is normal,
the occurrence and recurrence risks for
each child are one half. It is important to
keep in mind that each birth is an
independent event, as in the coin-tossing
examples. Thus, even though parents
may have already had a
child with the disease, their recurrence
risk remains one half. Even if they have
had several children, all affected (or all
unaffected) with the disease, the law of
independence dictates that the
probability that their next child will have
the disease is still one half. Although this
concept may seem intuitively obvious, it
is frequently misunderstood by the lay
A diagram of autosomal dominant
Par- ×
Aa aa

1 : 1
The recurrence risk for autosomal
dominant disorders is 50%. Because of
independence, this risk remains constant
no matter how many affected or
unaffected children are born.
4.2.2 Autosomal recessive (AR)
aa —affected.
Aa —carrier.
a — mutant gene on autosome.
Carrier: an individual who has a copy
of a disease-causing gene but does not
express the disease. The term is usually
used to denote heterozygotes for a
recessive disease gene.
A pedigree demonstrating the pattern of the
autosomal recessive inheritance.
Characteristics of autosomal recessive
·As in autosomal dominant inheritance,
usually males and females are equally
likely to be affected.
·Unlike autosomal dominant diseases,
in which the disease phenotype is seen in
one generation after another, autosomal
recessive diseases are usually seen in one
or more siblings but not in earlier
·On average, one fourth of the offspring
of two heterozygous carriers will be
affected with the disorder.
Like autosomal dominant diseases,
autosomal recessive diseases are fairly
rare in populations. Heterozygous
carriers for recessive disease genes are
much more common than affected
homozygotes. Consequently, the parents
of individuals affected with autosomal
recessive diseases are usually both
beterozygous carriers. One fourth of
their offspring will be normal
homozygotes, half will be phenotypically
normal carrier heterozygotes, and one
fourth will be homozygotes affected with
the disease (on average).
Figure illustrating the mating of two heterozygous
carriers of an autosomal recessive gene. The
genotype of affected offspring is shaded.
·Consanguinity is present more often in
pedigrees involving autosomal recessive
diseases than in those involving other
types of inheritance.
The term consanguinity refers to the
mating of related individuals. It is often a
factor in recessive disease because
related individuals are more likely to
share the same disease genes.
Autosomal recessive inheritance is
characterized by observation of the
disease phenotype in one or more siblings,
but the disease is not usually seen among
parents or other ancestors. Equal numbers
of affected males and females are usually
seen, and consanguinity may be present.
For example: Phenylketonuria (PKU).
Mutations at the locus encoding the
metabolic enzyme phenylalanine
hydroxylase render the homozygote
unable to metabolize the amino acid
phenylalanine. Although PKU babies are
normal at birth, their metabolic
deficiency produces a buildup of
phenylalanine and various toxic
metabolites. This is highly destructive to
the central nervous system, and it
eventually produces severe mental
A child with phenylketonuria. Mental retardation.
Another example: Hurler syndrome.
Hurler syndrome, an autosomal
recessive disorder resulting from a
deficiency of the lysosomal enzyme, α-L-
iduronidase. This enzyme deficiency
results in a buildup of
mucopolysaccharides in the lysosomes,
leading to skeletal abnormalities, short
stature, mental retardation, and coarse
facial features.
A child with Hurler syndrome. Note the
low, flat nasal root, thickened lips, widely
spaced teeth, and facial fullness.
Recurrence Risks.
As already mentioned the most
common mating type seen in recessive
disease involves two heterozygous carrier
parents. One fourth of the offspring from
this mating will be homozygous for the
disease gene and thus affected. The
recurrence risk for the offspring of
carrier parents is then 25%.
Occasionally a carrier of a recessive
disease gene mates with an individual
homozygous for the disease gene. In this
case roughly half of their children will be
affected, and half will be heterozygous
carriers. The recurrence risk is 50%.
A diagram of autosomal recessive
Par- × ×



1 : 1 : 1 : 1 1 : 1
The recurrence risk for autosomal
recessive diseases is usually 25%. When
an affected homozygote mates with a
heterozygote, the recurrence risk is 50%.