CHAPTER 7

Patterns of
Inheritance

That the fundamental aspects of heredity should

Family Studies
have turned out to be so extraordinarily simple
If we wish to investigate whether a particular trait or dis- supports us in the hope that nature may, after all,
order in humans is genetic and hereditary, we usually have
be entirely approachable.
to rely either on observation of the way in which it is trans-
THOMAS MORGAN (1919)
mitted from one generation to another, or on study of its
frequency among relatives.
An important reason for studying the pattern of inheri-
tance of disorders within families is to enable advice to be
given to members of a family regarding the likelihood of A trait or disorder that is determined by a gene on an
their developing it or passing it on to their children (i.e., autosome is said to show autosomal inheritance, whereas a
genetic counseling; see Chapter 17). Taking a family history trait or disorder determined by a gene on one of the sex
can, in itself, provide a diagnosis. For example, a child could chromosomes is said to show sex-linked inheritance.
come to the attention of a doctor with a fracture after a
seemingly trivial injury. A family history of relatives with a
Autosomal Dominant Inheritance
similar tendency to fracture and blue sclerae would suggest An autosomal dominant trait is one that manifests in the
the diagnosis of osteogenesis imperfecta. In the absence of heterozygous state, that is, in a person possessing both an
a positive family history, other diagnoses would have to be abnormal or mutant allele and the normal allele. It is often
considered. possible to trace a dominantly inherited trait or disorder
through many generations of a family (Figure 7.2). In South
Pedigree Drawing and Terminology Africa the vast majority of cases of porphyria variegata can
A family tree is a shorthand system of recording the perti- be traced back to one couple in the late seventeenth century.
nent information about a family. It usually begins with the This is a metabolic disorder characterized by skin blistering
person through whom the family came to the attention of as a result of increased sensitivity to sunlight (Figure 7.3),
the investigator. This person is referred to as the index case, and the excretion of urine that becomes ‘port wine’ colored
proband, or propositus; or, if female, the proposita. The on standing as a result of the presence of porphyrins
position of the proband in the family tree is indicated by an (p. 179). This pattern of inheritance is sometimes referred
arrow. Information about the health of the rest of the family to as ‘vertical’ transmission and is confirmed when male–
is obtained by asking direct questions about brothers, sisters, male (i.e., father to son) transmission is observed.
parents, and maternal and paternal relatives, with the rel-
evant information about the sex of the individual, affection
Genetic Risks
status, and relationship to other individuals being carefully Each gamete from an individual with a dominant trait or
recorded in the pedigree chart (Figure 7.1). Attention to disorder will contain either the normal allele or the mutant
detail can be crucial because patients do not always appreci- allele. If we represent the dominant mutant allele as ‘D’ and
ate the important difference between siblings and half- the normal allele as ‘d’, then the possible combinations of
siblings, or might overlook the fact, for example, that the the gametes is seen in Figure 7.4. Any child born to a person
child of a brother who is at risk of Huntington disease is affected with a dominant trait or disorder has a 1 in 2 (50%)
actually a step-child and not a biological relative. chance of inheriting it and being similarly affected. These
diagrams are often used in the genetic clinic to explain
segregation to patients and are more user-friendly than a
Mendelian Inheritance Punnett square (see Figs. 1.3 and 8.1).
More than 16,000 traits or disorders in humans exhibit
single gene unifactorial or mendelian inheritance. However,
Pleiotropy
characteristics such as height, and many common familial Autosomal dominant traits may involve only one organ or
disorders, such as diabetes or hypertension, do not usually part of the body, for example the eye in congenital cataracts.
follow a simple pattern of mendelian inheritance (see It is common, however, for autosomal dominant disorders
Chapter 9). to manifest in different systems of the body in a variety of
109
110 Patterns of Inheritance

Individuals

Normal Pregnancy
(male, female, unknown sex) (LMP or gestation) P P P
LMP 20 wk
01/06/97

Affected individual

Proband

With >2 conditions

P P P

Multiple individuals Consultand

(number known) 5 5 5

Multiple individuals
(number unknown) n n n Spontaneous
abortion Male Female

Deceased individual Affected spontaneous

abortion Male Female

Stillbirth
(gestation) Termination
SB of pregnancy
Male Female
28 wk
Relationships

Mating Twins
Zygosity
MZ DZ unknown

Relationship no ?
longer exists

No children
Consanguineous
mating
Azoospermia
Infertility
Biological parents (reason)
known

Adoption in Adoption out

Biological parents
unknown

Assisted reproductive scenarios

Sperm donation D Surrogate mother S

P P

Ovum donation Surrogate ovum donation D

D

P P
FIGURE 7.1 Symbols used to represent individuals and relationships in family trees.
 Patterns of Inheritance 111

I ways. This is pleiotropy—a single gene that may give rise to

two or more apparently unrelated effects. In tuberous
sclerosis affected individuals can present with a range of
II problems including learning difficulties, epilepsy, a facial
rash known as adenoma sebaceum (histologically composed
III of blood vessels and fibrous tissue known as angiokeratoma)
or subungual fibromas (Figure 7.5); some affected individu-
IV als have all features, whereas others may have almost none.
Some discoveries are challenging our conceptual under-
Affected standing of the term pleiotropy on account of the remark-
FIGURE 7.2 Family tree of an autosomal dominant trait. Note ably diverse syndromes that can result from different
the presence of male-to-male transmission. mutations in the same gene—for example, the LMNA gene
(which encodes lamin A/C) and the X-linked filamin A

FIGURE 7.3 Blistering skin lesions on the hand in porphyria

variegata.

Affected parent Normal parent

D d d d A

D d d d D d d d

Affected Normal Affected Normal

B
FIGURE 7.4 Segregation of alleles in autosomal dominant inher- FIGURE 7.5 The facial rash (A) of angiokeratoma (adenoma
itance. D represents the mutated allele, whereas d represents the sebaceum) in a male with tuberous sclerosis, and a typical sub-
normal allele. ungual fibroma of the nail bed (B).
112 Patterns of Inheritance

no abnormal clinical features, representing so-called reduced

penetrance or what is commonly referred to in lay terms as
‘skipping a generation’. Reduced penetrance is thought to
be the result of the modifying effects of other genes, as well
as interaction of the gene with environmental factors. An
individual who has no features of a disorder despite being
heterozygous for a particular gene mutation is said to rep-
resent non-penetrance.
Reduced penetrance and variable expressivity, together
with the pleiotropic effects of a mutant allele, all need to
be taken into account when trying to interpret family
history information for disorders that follow autosomal
dominant inheritance. A good example of a very variable
condition for which non-penetrance is frequently seen is
Treacher-Collins syndrome. In its most obvious manifesta-
tion the facial features are unmistakable (Figure 7.7).
However, the mother of the child illustrated is also known
FIGURE 7.6 Dunnigan-type familial partial lipodystrophy due to to harbor the gene (TCOF1) mutation as she has a number
a mutation in the lamin A/C gene. The patient lacks adipose of close relatives with the same condition.
tissue, especially in the distal limbs. A wide variety of clinical
phenotypes is associated with mutations in this one gene.

(FLNA) gene. Mutations in LMNA may cause Emery-

Dreifuss muscular dystrophy, a form of limb girdle muscular
dystrophy, a form of Charcot-Marie-Tooth disease (p. 305),
dilated cardiomyopathy (p. 296) with conduction abnor-
mality, Dunnigan-type familial partial lipodystrophy (Figure
7.6), mandibuloacral dysplasia, and a very rare condition
that has always been a great curiosity—Hutchinson-Gilford
progeria. These are due to heterozygous mutations, with
the exception of the Charcot-Marie-Tooth disease and
mandibuloacral dysplasia, which are recessive—affected
individuals are therefore homozygous for LMNA mutations.
Sometimes an individual with a mutation is entirely normal.
Mutations in the filamin A gene have been implicated
in the distinct, though overlapping, X-linked dominant dys-
morphic conditions oto-palato-digital syndrome, Melnick-
Needles syndrome and frontometaphyseal dysplasia.
However, it could not have been foreseen that a form of
X-linked dominant epilepsy in women, called periventricu-
lar nodular heterotopia, is also due to mutations in this gene.

Variable Expressivity
The clinical features in autosomal dominant disorders can
show striking variation from person to person, even in the
same family. This difference between individuals is referred
to as variable expressivity. In autosomal dominant polycys-
tic kidney disease, for example, some affected individuals
develop renal failure in early adulthood whereas others have FIGURE 7.7 The baby in this picture has Treacher-Collins syn-
just a few renal cysts that do not affect renal function drome, resulting from a mutation in TCOF1. The mandible is
significantly. small, the palpebral fissures slant downward, there is usually a
defect (coloboma) of the lower eyelid, the ears may show micro-
Reduced Penetrance tia, and hearing impairment is common. The condition follows
autosomal dominant inheritance but is very variable—the baby’s
In some individuals heterozygous for gene mutations giving mother also has the mutation but she shows no obvious signs
rise to certain autosomal dominant disorders, there may be of the condition.
 Patterns of Inheritance 113

I
New Mutations
In autosomal dominant disorders an affected person usually
has an affected parent. However, this is not always the case II
and it is not unusual for a trait to appear in an individual
when there is no family history of the disorder. A striking III
example is achondroplasia, a form of short-limbed dwarfism
(pp. 93–94), in which the parents usually have normal IV
stature. The sudden unexpected appearance of a condition
arising as a result of a mistake occurring in the transmission Affected Consanguineous mating
of a gene is called a new mutation. The dominant mode of FIGURE 7.8 Family tree of an autosomal recessive trait.
inheritance of achondroplasia could be confirmed only by
the observation that the offspring of persons with achon-
droplasia had a 50% chance of having achondroplasia. In less heterozygotes—e.g., Huntington disease (p. 293) and myo-
dramatic conditions other explanations for the ‘sudden’ tonic dystrophy (p. 295).
appearance of a disorder must be considered. This includes
non-penetrance and variable expression, as mentioned in
Autosomal Recessive Inheritance
the previous section. However, the astute clinician also Recessive traits and disorders are manifest only when the
needs to be aware that the family relationships may not be mutant allele is present in a double dose (i.e., homozygos-
as stated—i.e., there may be undisclosed non-paternity ity). Individuals heterozygous for such mutant alleles show
(p. 342) (or, occasionally, non-maternity). no features of the disorder and are perfectly healthy; they
New dominant mutations, in certain instances, have been are described as carriers. The family tree for recessive traits
associated with an increased age of the father. Traditionally, (Figure 7.8) differs markedly from that seen in autosomal
this is believed to be a consequence of the large number of dominant traits. It is not possible to trace an autosomal
mitotic divisions that male gamete stem cells undergo recessive trait or disorder through the family, as all the
during a man’s reproductive lifetime (p. 41). However, this affected individuals in a family are usually in a single sibship
may well be a simplistic view. In relation to mutations in (i.e., brothers and sisters). This is sometimes referred to as
FGFR2 (craniosynostosis syndromes), ground-breaking ‘horizontal’ transmission, but this is an inappropriate and
work by Wilkie’s group in Oxford demonstrated that caus- misleading term.
ative gain-of-function mutations confer a selective advan-
tage to spermatogonial stem cells, so that mutated cell lines
Consanguinity
accumulate in the testis. Enquiry into the family history of individuals affected with
rare recessive traits or disorders might reveal that their
Co-Dominance parents are related (i.e., consanguineous). The rarer a
Co-dominance is the term used for two allelic traits that recessive trait or disorder, the greater the frequency of
are both expressed in the heterozygous state. In persons consanguinity among the parents of affected individuals. In
with blood group AB it is possible to demonstrate both cystic fibrosis, the most common ‘serious’ autosomal reces-
A and B blood group substances on the red blood cells, sive disorder in western Europeans (p. 1), the frequency
so the A and B blood groups are therefore co-dominant of parental consanguinity is only slightly greater than that
(p. 205). seen in the general population. By contrast, in alkaptonuria,
one of the original inborn errors of metabolism (p. 171),
Homozygosity for Autosomal Dominant Traits which is an exceedingly rare recessive disorder, Bateson and
The rarity of most autosomal dominant disorders and dis- Garrod, in their original description of the disorder, observed
eases means that they usually occur only in the heterozy- that one-quarter or more of the parents were first cousins.
gous state. There are, however, a few reports of children They reasoned that rare alleles for disorders such as alkap-
born to couples where both parents are heterozygous tonuria are more likely to ‘meet up’ in the offspring of
for a dominantly inherited disorder. Offspring of such cousins than in the offspring of parents who are unrelated.
couples are, therefore, at risk of being homozygous. In some In large inbred kindreds an autosomal recessive condition
instances, affected individuals appear either to be more may be present in more than one branch of the family.
severely affected, as has been reported with achondroplasia,
or to have an earlier age of onset, as in familial hypercho-
Genetic Risks
lesterolemia (p. 175). The heterozygote with a phenotype If we represent the normal dominant allele as ‘R’ and the
intermediate between the homozygotes for the normal and recessive mutant allele as ‘r’, then each parental gamete
mutant alleles is consistent with a haploinsufficiency loss- carries either the mutant or the normal allele (Figure 7.9).
of-function mutation (p. 26). The various possible combinations of gametes mean that the
Conversely, with other dominantly inherited disorders, offspring of two heterozygotes have a 1 in 4 (25%) chance
homozygous individuals are not more severely affected than of being homozygous affected, a 1 in 2 (50%) chance of
114 Patterns of Inheritance

Carrier father Carrier mother often choose to have children with another deaf person.
It would be expected that, if two deaf persons were homo-
zygous for the same recessive gene, all of their children
would be similarly affected. Families have been described
in which all the children born to parents who are deaf due
to autosomal recessive genes have had perfectly normal
R r R r hearing because they are double heterozygotes. The expla-
nation is that the parents were homozygous for mutant
alleles at different loci (i.e., different genes can cause auto-
somal recessive sensorineural deafness). In fact, over the
past 10 to 15 years, approximately 30 genes and a further
50 loci have been shown to be involved. A very similar story
applies to autosomal recessive retinitis pigmentosa, and to
R R R r R r r r
a lesser extent primary autosomal recessive microcephaly.
Disorders with the same phenotype from different
genetic loci are known as genocopies, whereas, when the
same phenotype results from environmental causes it is
known as a phenocopy.
Normal Carrier Carrier Affected Mutational Heterogeneity
FIGURE 7.9 Segregation of alleles in autosomal recessive inheri-
tance. R represents the normal allele, r the mutated allele. Heterogeneity can also occur at the allelic level. In the
majority of single-gene disorders (e.g., β-thalassemia) a
large number of different mutations have been identified as
being heterozygous unaffected, and a 1 in 4 (25%) chance being responsible (p. 160). There are individuals who have
of being homozygous unaffected. two different mutations at the same locus and are known
as compound heterozygotes, constituting what is known as
Pseudodominance allelic or mutational heterogeneity. Most individuals
If an individual who is homozygous for an autosomal reces- affected with an autosomal recessive disorder are probably
sive disorder has children with a carrier of the same disor- compound heterozygotes rather than true homozygotes,
der, their offspring have a 1 in 2 (50%) chance of being unless their parents are related, when they are likely to be
affected. Such a pedigree is said to exhibit pseudodomi- homozygous for the same mutation by descent, having
nance (Figure 7.10). inherited the same mutation from a common ancestor.

Locus Heterogeneity Sex-Linked Inheritance

A disorder inherited in the same manner can be due to Sex-linked inheritance refers to the pattern of inheritance
mutations in more than one gene, or what is known as locus shown by genes that are located on either of the sex chro-
heterogeneity. For example, it is recognized that sensori- mosomes. Genes carried on the X chromosome are referred
neural hearing impairment/deafness most commonly shows to as being X-linked, and those carried on the Y chromo-
autosomal recessive inheritance. Deaf persons, by virtue of some are referred to as exhibiting Y-linked or holandric
their schooling and involvement in the deaf community, inheritance.

X-Linked Recessive Inheritance

An X-linked recessive trait is one determined by a gene
I
1 2
carried on the X chromosome and usually manifests only in
males. A male with a mutant allele on his single X chromo-
some is said to be hemizygous for that allele. Diseases
inherited in an X-linked manner are transmitted by healthy
heterozygous female carriers to affected males, as well as
II by affected males to their obligate carrier daughters, with
1 2 a consequent risk to male grandchildren through these
daughters (Figure 7.11). This type of pedigree is sometimes
Homozygous
said to show ‘diagonal’ or a ‘knight’s move’ pattern of
Heterozygous transmission.
The mode of inheritance whereby only males are affected
FIGURE 7.10 A pedigree with a woman (I2) homozygous for an
autosomal recessive disorder whose husband is heterozygous for by a disease that is transmitted by normal females was
the same disorder. They have a homozygous affected daughter appreciated by the Jews nearly 2000 years ago. They
so that the pedigree shows pseudodominant inheritance. excused from circumcision the sons of all the sisters of a
 Patterns of Inheritance 115

I Normal father Carrier mother

II

III
X Y X Xr
IV

Affected
Carrier
FIGURE 7.11 Family tree of an X-linked recessive trait in which
affected males reproduce.

X X X Y X Xr Xr Y

mother who had sons with the ‘bleeding disease’, in other

words, hemophilia (p. 309). The sons of the father’s siblings
were not excused. Queen Victoria was a carrier of hemo-
philia, and her carrier daughters, who were perfectly healthy, Normal Normal Carrier Affected
introduced the gene into the Russian and Spanish royal daughter son daughter son
families. Fortunately for the British royal family, Queen FIGURE 7.13 Segregation of alleles in X-linked recessive inheri-
Victoria’s son, Edward VII, did not inherit the gene and so tance, relating to the offspring of a carrier female. r represents
could not transmit it to his descendants. the mutated allele.

Genetic Risks
A male transmits his X chromosome to each of his daugh- For a carrier female of an X-linked recessive disorder
ters and his Y chromosome to each of his sons. If a male having children with a normal male, each son has a 1 in 2
affected with hemophilia has children with a normal female, (50%) chance of being affected and each daughter has a 1
then all of his daughters will be obligate carriers but none in 2 (50%) chance of being a carrier (Figure 7.13).
of his sons will be affected (Figure 7.12). A male cannot Some X-linked disorders are not compatible with sur-
transmit an X-linked trait to his son, with the very rare vival to reproductive age and are not, therefore, transmitted
exception of uniparental heterodisomy (p. 121). by affected males. Duchenne muscular dystrophy is the
commonest muscular dystrophy and is a severe disease
(p. 307). The first sign is delayed walking followed by a
Affected father Normal mother waddling gait, difficulty in climbing stairs unaided, and a
tendency to fall easily. By about the age of 10 years affected
boys usually need to use a wheelchair. The muscle weakness
progresses gradually and affected males ultimately become
confined to bed and often die in their late teenage years or
early 20s (Figure 7.14). Because affected boys do not
Xr Y X X usually survive to reproduce, the disease is transmitted by
healthy female carriers (Figure 7.15), or may arise as a new
mutation.

Variable Expression in Heterozygous Females

In humans, several X-linked disorders are known in which
heterozygous females have a mosaic phenotype with a
mixture of features of the normal and mutant alleles. In
X Xr X Y X Xr X Y
X-linked ocular albinism, the iris and ocular fundus of
affected males lack pigment. Careful examination of the
ocular fundus in females heterozygous for ocular albinism
reveals a mosaic pattern of pigmentation (see Figure 6.25,
p. 104). This mosaic pattern of involvement can be explained
Carrier Normal Carrier Normal
daughter son daughter son by the random process of X-inactivation (p. 103). In the
FIGURE 7.12 Segregation of alleles in X-linked recessive inheri- pigmented areas, the normal gene is on the active X chro-
tance, relating to the offspring of an affected male. r represents mosome, whereas in the depigmented areas the mutant
the mutated allele. allele is on the active X chromosome.
116 Patterns of Inheritance

green. About 8% of males are red-green color blind and,

although it is unusual, because of the high frequency of this
allele in the population about 1 in 150 women are red-green
color-blind by virtue of both parents having the allele on the
X chromosome. Therefore, a female can be affected with
an X-linked recessive disorder as a result of homozygosity
for an X-linked allele, although the rarity of most X-linked
conditions means that the phenomenon is uncommon. A
female could also be homozygous if her father was affected
and her mother was normal, but a new mutation occurred
on the X chromosome transmitted to the daughter; alter-
natively, it could happen if her mother was a carrier and her
father was normal, but a new mutation occurred on the X
chromosome he transmitted to his daughter—but these
scenarios are rare.

Skewed X-Inactivation. The process of X-inactivation

(p. 103) usually occurs randomly, there being an equal
chance of either of the two X chromosomes in a hetero-
zygous female being inactivated in any one cell. After
X-inactivation in embryogenesis, therefore, in roughly half
the cells one of the X chromosomes is active, whereas in
the other half it is the other X chromosome that is active.
Sometimes this process is not random, allowing for the
possibility that the active X chromosome in most of the
cells of a heterozygous female carrier is the one bearing
the mutant allele. If this happens, a carrier female would
exhibit some of the symptoms and signs of the disease and
be a so-called manifesting heterozygote or carrier. This has
been reported in a number of X-linked disorders, including
FIGURE 7.14 Boy with Duchenne muscular dystrophy; note the
Duchenne muscular dystrophy and hemophilia A (pp. 307,
enlarged calves and wasting of the thigh muscles.
309). In addition, there are reports of several X-linked
disorders in which there are a number of manifesting car-
riers in the same family, consistent with the coincidental
Females Affected with X-Linked Recessive Disorders
inheritance of an abnormality of X-inactivation (p. 204).
Occasionally a woman might manifest features of an
X-linked recessive trait. There are several explanations for Numerical X-Chromosome Abnormalities. A female could
how this can happen. manifest an X-linked recessive disorder by being a carrier
of an X-linked recessive mutation and having only a single
Homozygosity for X-Linked Recessive Disorders. A com- X chromosome (i.e., Turner syndrome, see p. 207). Women
mon X-linked recessive trait is red–green color blindness with Turner syndrome and hemophilia A or Duchenne mus-
—the inability to distinguish between the colors red and cular dystrophy have been reported occasionally.

X-Autosome Translocations. Females with a translocation

involving one of the X chromosomes and an autosome can
I be affected with an X-linked recessive disorder. If the
breakpoint of the translocation disrupts a gene on the
X chromosome, then a female can be affected. This is
II
because the X chromosome involved in the translocation
survives preferentially so as to maintain functional disomy
III of the autosomal genes (Figure 7.16). The observation of
females affected with Duchenne muscular dystrophy with
IV Affected X-autosome translocations involving the same region of the
Carrier short arm of the X chromosome helped to map the
FIGURE 7.15 Family tree of Duchenne muscular dystrophy with Duchenne muscular dystrophy gene (p. 307). This type of
the disorder being transmitted by carrier females and affecting observation has been vital in the positional cloning of a
males, who do not survive to transmit the disorder. number of genes in humans (p. 75).
 Patterns of Inheritance 117

Break disorder there is an excess of affected females and direct

points male-to-male transmission cannot occur.
Xp2 1 An example of an X-linked dominant trait is X-linked
hypophosphatemia, also known as vitamin D–resistant
rickets. Rickets can be due to a dietary deficiency of vitamin
D, but in vitamin D–resistant rickets the disorder occurs
even when there is an adequate dietary intake of vitamin
D. In the X-linked dominant form of vitamin D–resistant
rickets, both males and females are affected with short
Autosomes X chromosomes
stature due to short and often bowed long bones, although
the females usually have less severe skeletal changes than
the males. The X-linked form of Charcot-Marie-Tooth
disease (hereditary motor and sensory neuropathy) is
another example.
A mosaic pattern of involvement can be demonstrated
in females heterozygous for some X-linked dominant disor-
ders. An example is the mosaic pattern of abnormal pig-
mentation of the skin that follows developmental lines seen
A B in females heterozygous for the X-linked dominant disorder
50% 50%
incontinentia pigmenti (Figure 7.18). This is also an example
of a disorder that is usually lethal for male embryos that
inherit the mutated allele. Others include the neurological
I conditions Rett syndrome and periventricular nodular
N heterotopia.
A
C Y-Linked Inheritance
T Y-linked or holandric inheritance implies that only males
I are affected. An affected male transmits Y-linked traits to
V all of his sons but to none of his daughters. In the past it
A has been suggested that bizarre-sounding conditions such
T as porcupine skin, hairy ears and webbed toes are Y-linked
A B A B
I traits. With the possible exception of hairy ears, these
Normal O Derivative
X chromosome X chromosome claims of holandric inheritance have not stood up to more
inactivated N inactivated careful study. Evidence clearly indicates, however, that the
H-Y histocompatibility antigen (p. 200) and genes involved
in spermatogenesis are carried on the Y chromosome and,
Cells survive with Cell death due to therefore, manifest holandric inheritance. The latter, if
breakpoint at Xp21 leading inactivation of deleted, leads to infertility from azoospermia (absence of
to development of DMD autosome segment
the sperm in semen) in males. The recent advent of tech-
FIGURE 7.16 Generation of an X-autosome translocation with
breakpoint in a female and how this results in the development niques of assisted reproduction, particularly the technique
of Duchenne muscular dystrophy. of intracytoplasmic sperm injection (ICSI), means that, if
a pregnancy with a male conceptus results after the use of
this technique, the child will also necessarily be infertile.

X-Linked Dominant Inheritance

Although uncommon, there are disorders that are manifest I
in the heterozygous female as well as in the male who has
the mutant allele on his single X chromosome. This is
known as X-linked dominant inheritance (Figure 7.17). II
X-linked dominant inheritance superficially resembles that
of an autosomal dominant trait because both the daughters III
and sons of an affected female have a 1 in 2 (50%) chance
of being affected. There is, however, an important differ- IV
ence. With an X-linked dominant trait, an affected male
transmits the trait to all his daughters but to none of his Affected
sons. Therefore, in families with an X-linked dominant FIGURE 7.17 Family tree of an X-linked dominant trait.
118 Patterns of Inheritance

somal dominant traits, males being predominantly affected

in both cases. The influence of sex in these two examples
is probably through the effect of male hormones. Gout,
for example, is very rare in women before the menopause
but the frequency increases in later life. Baldness does not
occur in males who have been castrated. In hemochroma-
tosis (p. 244), the most common autosomal recessive dis-
order in Western society, homozygous females are much
less likely than homozygous males to develop iron overload
and associated symptoms; the explanation usually given is
that women have a form of natural blood loss through
menstruation.

Sex Limitation
Sex limitation refers to the appearance of certain features
only in individuals of a particular sex. Examples include
virilization of female infants affected with the autosomal
recessive endocrine disorder, congenital adrenal hyperplasia
(p. 174).

Establishing the Mode of Inheritance

of a Genetic Disorder
In experimental animals it is possible to arrange specific
types of mating to establish the mode of inheritance of a
FIGURE 7.18 Mosaic pattern of skin pigmentation in a female trait or disorder. In humans, when a disorder is newly rec-
with the X-linked dominant disorder, incontinentia pigmenti. ognized, the geneticist approaches the problem indirectly
The patient has a mutation in a gene on one of her X chromo-
by fitting likely models of inheritance to the observed
somes; the pigmented areas indicate tissue in which the normal
X chromosome has been inactivated. This developmental outcome in the offspring. Certain features are necessary to
pattern follows Blaschko’s lines (see Chapter 18, p. 276). support a particular mode of inheritance. Formally estab-
lishing the mode of inheritance is not usually possible with
a single family and normally requires study of a number of
Partial Sex-Linkage
families (Box 7.1).
Partial sex-linkage has been used in the past to account for
certain disorders that appear to exhibit autosomal dominant
inheritance in some families and X-linked inheritance in
Box 7.1 Features that Support the Single-Gene
others. This is now known to be likely to be because of
or Mendelian Patterns of Inheritance
genes carried on that portion of the X chromosome sharing
homology with the Y chromosome, and which escapes Autosomal Dominant
X-inactivation. During meiosis, pairing occurs between the Males and females affected in equal proportions
homologous distal parts of the short arms of the X and Affected individuals in multiple generations
Transmission by individuals of both sexes (i.e., male to male,
Y chromosomes, the so-called pseudoautosomal region. As
female to female, male to female, and female to male)
a result of a cross-over, a gene could be transferred from the
Autosomal Recessives
X to the Y chromosome, or vice versa, allowing the possibil- Males and females affected in equal proportions
ity of male-to-male transmission. The latter instances would Affected individuals usually in only a single generation
be consistent with autosomal dominant inheritance. A rare Parents can be related (i.e., consanguineous)
skeletal dysplasia, Leri-Weil dyschondrosteosis, in which X-Linked Recessive
affected individuals have short stature and a characteristic Only males usually affected
Transmitted through unaffected females
wrist deformity (Madelung deformity), has been reported
Males cannot transmit the disorder to their sons (i.e., no
to show both autosomal dominant and X-linked inheritance. male-to-male transmission)
The disorder has been shown to be due to deletions of, or X-Linked Dominant
mutations in, the short stature homeobox (SHOX) gene, Males and females affected but often an excess of females
which is located in the pseudoautosomal region. Females less severely affected than males
Affected males can transmit the disorder to their daughters but
Sex Influence not to sons
Y-Linked Inheritance
Some autosomal traits are expressed more frequently in
Affected males only
one sex than in another—so-called sex influence. Gout and Affected males must transmit it to their sons
presenile baldness are examples of sex-influenced auto-
 Patterns of Inheritance 119

Autosomal Dominant Inheritance Multiple Alleles and Complex Traits

To determine whether a trait or disorder is inherited in an So far, each of the traits we have considered has involved
autosomal dominant manner, there are three specific fea- only two alleles, the normal, and the mutant. However,
tures that need to be observed. First, it should affect some traits and diseases are neither monogenic nor poly-
both males and females in equal proportions. Second, it genic. Some genes have more than two allelic forms (i.e.,
is transmitted from one generation to the next. Third, multiple alleles). Multiple alleles are the result of a normal
all forms of transmission between the sexes are observed gene having mutated to produce various different alleles,
(i.e., male to male, female to female, male to female, some of which can be dominant and others recessive to the
and female to male). Male-to-male transmission excludes normal allele. In the case of the ABO blood group system
the possibility of the gene being on the X chromosome. (p. 205), there are at least four alleles (A1, A2, B, and O).
In the case of sporadically occurring disorders, increased An individual can possess any two of these alleles, which
paternal age may suggest a new autosomal dominant may be the same or different (AO, A2B, OO, and so on).
mutation. Alleles are carried on homologous chromosomes and there-
fore a person transmits only one allele for a certain trait to
Autosomal Recessive Inheritance any particular offspring. For example, a person with the
There are three features that suggest the possibility of genotype AB will transmit to any particular offspring either
autosomal recessive inheritance. First, the disorder affects the A allele or the B allele, but never both or neither (Table
males and females in equal proportions. Second, it usually 7.1). This relates only to genes located on the autosomes
affects only individuals in one generation in a single sibship and does not apply to alleles on the X chromosome; in this
(i.e., brothers and sisters) and does not occur in previous instance a woman would have two alleles, either of which
and subsequent generations. Third, consanguinity in the could be transmitted to offspring, whereas a man only has
parents provides further support for autosomal recessive one allele to transmit.
inheritance. The dramatic advances in genome wide scanning using
multiple DNA probes has made it possible to begin inves-
X-Linked Recessive Inheritance tigating so-called complex traits (i.e., conditions that are
There are three main features necessary to establish X-linked usually much more common than mendelian disorders and
recessive inheritance. First, the trait or disorder should likely to be due to the interaction of more than one gene).
affect males almost exclusively. Second, X-linked recessive The effects may be additive, one may be rate limiting over
disorders are transmitted through unaffected carrier females the action of another, or one may enhance or multiply the
to their sons. Affected males, if they survive to reproduce, effect of another; this is considered in more detail in
can have affected grandsons through their daughters who Chapter 15. The possibility of a small number of gene loci
are obligate carriers. Thirdly, male-to-male transmission is being implicated in some disorders has given rise to the
not observed (i.e., affected males cannot transmit the dis- concept of oligogenic inheritance, examples of which
order to their sons). include the following.

X-Linked Dominant Inheritance Digenic Inheritance

There are three features necessary to establish X-linked This refers to the situation where a disorder has been shown
dominant inheritance. First, males and females are affected to be due to the additive effects of heterozygous mutations
but affected females are more frequent than affected males. at two different gene loci, a concept referred to as digenic
Second, females are usually less severely affected than inheritance. This is seen in certain transgenic mice. Mice
males. Third, although affected females can transmit the
disorder to both male and female offspring, affected males
can transmit the disorder only to their daughters (except
Table 7.1 Possible Genotypes, Phenotypes, and
in partial sex-linkage; see p. 118), all of whom will be
Gametes Formed from the Four Alleles
affected. In the case of X-linked dominant disorders that
A1, A2, B, and O at the ABO Locus
are almost invariably lethal in male embryos (e.g., inconti-
nentia pigmenti; see pp. 117–118), only females will be Genotype Phenotype Gametes
affected and families may show an excess of females over A1A1 A1 A1
males as well as a number of miscarriages that are the A2A2 A2 A2
affected male pregnancies. BB B B
OO O O
Y-Linked Inheritance A1A2 A1 A1 or A2
A1 B A1B A1 or B
There are two features necessary to establish a Y-linked A1O A1 A1 or O
pattern of inheritance. First, it affects only males. Second, A2B A2B A2 or B
affected males must transmit the disorder to their sons A2O A2 A2 or O
BO B B or O
(e.g., male infertility by ICSI) (p. 117).
120 Patterns of Inheritance

that are homozygotes for rv (rib-vertebrae) or Dll1

(Delta–like-1) manifest abnormal phenotypes, whereas
their respective heterozygotes are normal. However, mice
that are double heterozygotes for rv and Dll1 show verte-
bral defects. In humans, one form of retinitis pigmentosa,
a disorder of progressive visual impairment, is caused by
double heterozygosity for mutations in two unlinked genes,
ROM1 and Peripherin, which both encode proteins present
in photoreceptors. Individuals with only one of these muta-
tions are not affected. In the field of inherited cardiac
arrhythmias and cardiomyopathies (p. 304), it is becoming
clear that some cases of arrhythmogenic right ventricular
dysplasia exhibit digenic inheritance.

Triallelic Inheritance
Bardet–Biedl syndrome is a rare dysmorphic condition
(though relatively more common in some inbred communi-
ties) with obesity, polydactyly, renal abnormalities, retinal
pigmentation, and learning disability. Seven different gene
loci have been identified and, until recently, the syndrome
was thought to follow straightforward autosomal recessive FIGURE 7.19 Newborn baby with severe hypotonia requiring
inheritance. However, it is now known that one form ventilation as a result of having inherited myotonic dystrophy
occurs only when an individual who is homozygous for from his mother.
mutations at one locus is also heterozygous for mutation at
another Bardet-Biedl locus; this is referred to as triallelic
inheritance.
Other patterns of inheritance that are not classically Fragile X syndrome (CGG repeats) (p. 278) behaves in a
mendelian are also recognized and explain some unusual similar way, with major instability in the expansion occur-
phenomena. ring during maternal meiosis. A similar expansion—in this
case CAG repeats—in the 5′ end of the Huntington disease
gene (Figure 7.20) in paternal meiosis accounts for the
Anticipation increased risk of early onset Huntington disease, occasion-
In some autosomal dominant traits or disorders, such as ally in childhood or adolescence, when the gene is transmit-
myotonic dystrophy, the onset of the disease occurs at an ted by the father. The inherited spinocerebellar ataxia group
earlier age in the offspring than in the parents, or the disease of conditions is another example.
occurs with increasing severity in subsequent generations.
This phenomenon is called anticipation. It used to be
believed that this effect was the result of a bias of ascertain-
Mosaicism
ment, because of the way in which the families were col- An individual, or a particular tissue of the body, can consist
lected. It was argued that this arose because persons in of more than one cell type or line, through an error occur-
whom the disease begins earlier, or is more severe, are more ring during mitosis at any stage after conception. This is
likely to be ascertained and only those individuals who are known as mosaicism (p. 50). Mosaicism of either somatic
less severely affected tend to have children. In addition, it tissues or germ cells can account for some instances of
was thought that, because the observer is in the same gen- unusual patterns of inheritance or phenotypic features in an
eration as the affected presenting probands, many individu- affected individual.
als who at present are unaffected will, by necessity, develop
the disease later in life.
Somatic Mosaicism
Recent studies, however, have shown that in a number The possibility of somatic mosaicism is suggested by the
of disorders, including Huntington disease and myotonic features of a single-gene disorder being less severe in an
dystrophy, anticipation is, in fact, a real biological phenom- individual than is usual, or by being confined to a particular
enon occurring as a result of the expansion of unstable part of the body in a segmental distribution; for example,
triplet repeat sequences (p. 24). An expansion of the CTG as occurs occasionally in neurofibromatosis type I (p. 298).
triplet repeat in the 3′ untranslated end of the myotonic The timing of the mutation event in early development may
dystrophy gene, occurring predominantly in maternal determine whether it is transmitted to the next generation
meiosis, appears to be the explanation for the severe neo- with full expression—this will depend on the mutation
natal form of myotonic dystrophy that usually only occurs being present in all or some of the gonadal tissue, and hence
when the gene is transmitted by the mother (Figure 7.19). germline cells.
 Patterns of Inheritance 121

– the past decade, with the advent of DNA technology, some

individuals have been shown to have inherited both homo-
logs of a chromosome pair from only one of their parents,
so-called uniparental disomy. If an individual inherits two
copies of the same homolog from one parent, through an
error in meiosis II (p. 41), this is called uniparental isodi-
somy (Figure 7.21). If, however, the individual inherits the
two different homologs from one parent through an error
in meiosis I (p. 39), this is termed uniparental heterodi-
somy. In either instance, it is presumed that the conceptus
would originally be trisomic, with early loss of a chromo-
some leading to the ‘normal’ disomic state. One-third of
such chromosome losses, if they occurred with equal fre-
quency, would result in uniparental disomy. Alternatively,
it is postulated that uniparental disomy could arise as a
result of a gamete from one parent that does not contain
+ a particular chromosome homolog (i.e., a gamete that is
nullisomic), being ‘rescued’ by fertilization with a gamete
that, through a second separate chance error in meiosis, is
disomic.
Using DNA techniques, uniparental disomy has been
FIGURE 7.20 Silver staining of a 5% denaturing gel of the po-
lymerase chain reaction products of the CAG triplet in the 5’ shown to be the cause of a father with hemophilia having
untranslated end of the Huntington disease gene from an an affected son and of a child with cystic fibrosis being born
affected male and his wife, showing her to have two similar-sized to a couple in which only the mother was a carrier (with
repeats in the normal range (20 and 24 copies) and him to proven paternity!). Uniparental paternal disomy for chro-
have one normal-sized triplet repeat (18 copies) and an ex-
mosome 15 may be linked to either Prader-Willi or Angel-
panded triplet repeat (44 copies). The bands in the left lane are
standard markers to allow sizing of the CAG repeat. (Courtesy man syndrome, or for chromosome 11 with a proportion of
Alan Dodge, Regional DNA Laboratory, St. Mary’s Hospital, cases of the overgrowth condition known as the Beckwith-
Manchester, UK.) Wiedemann syndrome (see the following section).

Genomic Imprinting
Gonadal Mosaicism
Genomic imprinting is an epigenetic phenomenon, referred
There have been many reports of families with autosomal to in Chapter 6 (p. 103). Epigenetics and genomic imprint-
dominant disorders, such as achondroplasia and osteogen- ing give the lie to Thomas Morgan’s quotation at the start
esis imperfecta, and X-linked recessive disorders, such as of this chapter! Although it was originally thought that
Duchenne muscular dystrophy and hemophilia, in which genes on homologous chromosomes were expressed equally,
the parents are phenotypically normal, and the results of it is now recognized that different clinical features can
investigations or genetic tests have also all been normal, but result, depending on whether a gene is inherited from the
in which more than one of their children has been affected. father or from the mother. This ‘parent of origin’ effect is
The most favored explanation for these observations is referred to as genomic imprinting, and methylation of
gonadal, or germline, mosaicism in one of the parents; that DNA is thought to be the main mechanism by which
is, the mutation is present in a proportion of the gonadal or expression is modified. Methylation is the imprint applied
germline cells. An elegant example of this was provided by to certain DNA sequences in their passage through game-
the demonstration of a mutation in the collagen gene togenesis, although only a small proportion of the human
responsible for osteogenesis imperfecta in a proportion of genome is in fact subject to this process. The differential
individual sperm from a clinically normal father who had allele expression (i.e., maternal or paternal) may occur in
two affected infants with different partners. It is important all somatic cells, or in specific tissues or stages of develop-
to keep germline mosaicism in mind when providing ment. Thus far, at least 80 human genes are known to be
recurrence risks in genetic counseling for apparently imprinted and the regions involved are known as differen-
new autosomal dominant and X-linked recessive mutations tially methylated regions (DMRs). These DMRs include
(p. 343). imprinting control regions (ICRs) that control gene expres-
sion across imprinted domains.
Evidence of genomic imprinting has been observed
Uniparental Disomy in two pairs of well known dysmorphic syndromes:
An individual normally inherits one of a pair of Prader-Willi and Angelman syndromes (chromosome 15q),
homologous chromosomes from each parent (p. 39). Over and Beckwith-Wiedemann and Russell-Silver syndromes
122 Patterns of Inheritance

Meiosis I Meiosis I

Meiosis II Meiosis II

Fertilization Fertilization

Loss of Loss of
chromosome chromosome

Uniparental Uniparental
A isodisomy B heterodisomy
FIGURE 7.21 Mechanism of origin of uniparental disomy. A, Uniparental isodisomy occurring through a disomic gamete arising
from non-disjunction in meiosis II fertilizing a monosomic gamete with loss of the chromosome from the parent contributing the
single homolog. B, Uniparental heterodisomy occurring through a disomic gamete arising from non-disjunction in meiosis I fertilizing
a monosomic gamete with loss of the chromosome from the parent contributing the single homolog.

(chromosome 11p). The mechanisms giving rise to these

conditions, although complex, reveal much about imprint-
ing and are therefore now considered in a little detail.

Prader-Willi Syndrome
Prader-Willi syndrome (PWS) (p. 282) occurs in approxi-
mately 1 in 20,000 births and is characterized by short
stature, obesity, hypogonadism, and learning difficulty
(Figure 7.22). Approximately 50% to 60% of individuals
with PWS can be shown to have an interstitial deletion of
the proximal portion of the long arm of chromosome 15,
approximately 2 Mb at 15q11-q13, visible by conventional
cytogenetic means, and in a further 15% a submicroscopic
deletion can be demonstrated by fluorescent in-situ hybrid-
ization (see p. 34) or molecular means. DNA analysis has
revealed that the chromosome deleted is almost always the
paternally derived homolog. Most of the remaining 25%
to 30% of individuals with PWS, without a chromosome
deletion, have been shown to have maternal uniparental
disomy. Functionally, this is equivalent to a deletion in the
paternally derived chromosome 15. FIGURE 7.22 Female child with Prader-Willi syndrome.
 Patterns of Inheritance 123

Paternal allele
Centromere Telomere
PWS ICR
UBE3A
Antisense

5' 3'
SNURF/SNRPN UBE3A
MKRN3 NDN
AS ICR
MAGE-L2

Maternal allele
FIGURE 7.23 Molecular organization (simplified) at 15q11-q13: Prader-Willi syndrome (PWS) and Angelman syndrome (AS). The
imprinting control region (ICR) for this locus has two components. The more telomeric acts as the PWS ICR and contains the pro-
moter of SNURF/SNRPN. SNURF/SNRPN produces several long and complex transcripts, one of which is believed to be an RNA
antisense inhibitor of UBE3A. The more centromeric ICR acts as the AS ICR on UBE3A, which is the only gene whose maternal expres-
sion is lost in AS. The AS ICR also inhibits the PWS ICR on the maternal allele. The PWS ICR also acts on the upstream genes MKRN3,
MAGE-L2, and NDN, which are unmethylated (s) on the paternal allele but methylated (•) on the maternal allele.

It is now known that only the paternally inherited

allele of this critical region of 15q11-q13 is expressed. The
molecular organization of the region is shown in Figure 7.23.
PWS is a multigene disorder and in the normal situation the
small nuclear ribonucleoprotein polypeptide N (SNRPN)
and adjacent genes (MKRN3, etc.) are paternally expressed.
Expression is under the control of a specific ICR. Analysis
of DNA from patients with PWS and various submicro-
scopic deletions enabled the ICR to be mapped to a segment
of about 4 kb, spanning the first exon and promoter of
SNRPN and upstream reading frame (SNURF). The 3′ end
of the ICR is required for expression of the paternally
expressed genes and also the origin of the long SNURF/
SNRPN transcript. The maternally expressed genes are
not differentially methylated but they are silenced on the
paternal allele, probably by an antisense RNA generated
from SNURF/SNRPN. In normal cells, the 5′ end of the
ICR, needed for maternal expression and involved in
Angelman syndrome (see below), is methylated on the
maternal allele. A

Angelman Syndrome (AS)

Angelman syndrome (p. 282) occurs in about 1 in 15,000
births and is characterized by epilepsy, severe learning dif-
ficulties, an unsteady or ataxic gait, and a happy affect
(Figure 7.24). Approximately 70% of individuals with AS
have been shown to have an interstitial deletion of the same
15q11-q13 region as is involved in PWS, but in this case on
the maternally derived homolog. In a further 5% of indi-
viduals with AS, the syndrome can be shown to have arisen
through paternal uniparental disomy. Unlike PWS, the fea-
tures of AS arise through loss of a single gene, UBE3A. In
up to 10% of individuals with AS, mutations have been
identified in UBE3A, one of the ubiquitin genes, which
appears to be preferentially or exclusively expressed from
the maternally derived chromosome 15 in brain. How
mutations in UBE3A lead to the features seen in persons B
with AS is not clear, but could involve ubiquitin-mediated FIGURE 7.24 A, Female child with Angelman syndrome.
destruction of proteins in the central nervous system in B, Adult male with Angelman syndrome.
124 Patterns of Inheritance

1 2 3 4
Beckwith-Wiedemann Syndrome
Beckwith–Wiedemann syndrome (BWS) is a clinically het-
4.2 kb Maternal band
erogeneous condition whose main underlying characteristic
is overgrowth. First described in 1963 and 1964, the main
features are macrosomia (prenatal and/or postnatal over-
growth), macroglossia (large tongue), abdominal wall defect
(omphalocele, umbilical hernia, diastasis recti), and neona-
tal hypoglycemia (Figure 7.26). Hemihyperplasia may be
present, as well as visceromegaly, renal abnormalities, ear
anomalies (anterior earlobe creases, posterior helical pits)
and cleft palate, and there may be embryonal tumors (par-
ticularly Wilms tumor).
BWS is, in a way, celebrated in medical genetics because
of the multiple different (and complex) molecular mecha-
nisms that underlie it. Genomic imprinting, somatic mosa-
icism, and multiple genes are involved, all within a 1 Mb
0.9 kb Paternal band region at chromosome 11p15 (Figure 7.27). Within this
region lie two independently regulated imprinted domains.
FIGURE 7.25 Southern blot to detect methylations of SNRPN. The more telomeric (differentially methylated region 1
DNA digested with Xba I and Not I was probed with KB17, which [DMR1] under control of ICR1) contains paternally
hybridizes to a CpG island within exon a of SNRPN. Patient 1 expressed IGF2 (insulin growth factor 2) and maternally
has Prader-Willi syndrome, patient 2 has Angelman syndrome,
expressed H19. The more centromeric imprinted domain
and patients 3 and 4 are unaffected. (Courtesy A. Gardner,
Department of Molecular Genetics, Southmead Hospital, Bristol.) (DMR2, under control of ICR2) contains the maternally
expressed KCNQ1 (previously known as KvLQT1) and
CDKN1C genes, and the paternally expressed antisense
transcript KCNQ1OT1, the promoter for which is located
within the KCNQ1 gene.
Disruption to the normal regulation of methylation
can give rise to altered gene expression dosage and,
development, particularly where UBE3A is expressed most
strongly, namely the hippocampus and Purkinje cells of the
cerebellum. UBE3A is under control of the AS ICR (see
Figure 7.23), which was mapped slightly upstream of
SNURF/SNRPN through analysis of patients with AS who
had various different microdeletions.
About 2% of individuals with PWS and approximately
5% of those with AS have abnormalities of the ICR itself;
these patients tend to show the mildest phenotypes. Patients
in this last group, unlike the other three, have a risk of
recurrence. In the case of AS, if the mother carries the same
mutation as the child, the recurrence risk is 50%, but even
if she tests negative for the mutation, there is an appreciable
recurrence risk from gonadal mosaicism.
Rare families have been reported in which a translocation
of the proximal portion of the long arm of chromosome 15
is segregating. Depending on whether the translocation is
transmitted by the father or mother, affected offspring
within the family have had either PWS or AS. In approxi-
mately 10% of AS cases the molecular defect is unknown—
but it may well be that some of these alleged cases have a
different, albeit phenotypically similar, diagnosis.
In many genetics service laboratories a simple DNA test
is used to diagnose both PWS and AS, exploiting the dif-
ferential DNA methylation characteristics at the 15q11- FIGURE 7.26 Baby girl with Beckwith-Wiedemann syndrome.
q13 locus (Figure 7.25). Note the large tongue and umbilical hernia.
 Patterns of Inheritance 125

DMR2 Paternal allele DMR1

Centromere ICR1 Telomere

ICR2

CTCF CTCF Enhancer

5' 3'
Other CDKN1C CTCF KCNQ1 IGF2 CTCF H19
genes
KCNQ1OT1
Maternal allele
FIGURE 7.27 Molecular organization (simplified) at 11p15.5: Beckwith-Wiedemann and Russell-Silver syndromes. The region contains
two imprinted domains (DMR1 and DMR2) that are regulated independently. The ICRs are differentially methylated (• methylated;
s unmethylated). CCCTC-binding factor (CTCF) binds to the unmethylated alleles of both ICRs. In DMR1, coordinated regulation
leads to expression of IGF2 only on the paternal allele and H19 expression only on the maternal allele. In DMR2, coordinated regula-
tion leads to maternal expression of KCNQ1 and CDKN1C (plus other genes), and paternal expression of KCNQ1OT1 (a non-coding
RNA with antisense transcription to KCNQ1). Angled black arrows show the direction of the transcripts.

consequentially, features of BWS. In DMR1, gain of meth- Russell–Silver syndrome (RSS) cases are due to abnor-
ylation on the maternal allele leads to loss of H19 expres- malities of imprinting at the 11p.15.5 locus. Whereas
sion and biallelic IGF2 expression (i.e., effectively two hypermethylation of DMR1 leads to upregulated IGF2
copies of the paternal epigenotype). This occurs in up to and overgrowth, hypomethylation of H19 leads to down-
7% of BWS cases and is usually sporadic. In DMR2, loss of regulated IGF2, the opposite molecular and biochemical
methylation results in two copies of the paternal epigeno- consequence, and these patients have features of RSS.
type and a reduction in expression of CDKN1C; this mech- Interestingly, in contrast to BWS, there are no cases of RSS
anism is implicated in 50% to 60% of sporadic BWS cases. with altered methylation of the more centromeric DMR2
CDKN1C may be a growth inhibitory gene and mutations region.
have been found in 5% to 10% of cases of BWS. About 15%
of BWS cases are familial, and CDKN1C mutations are
found in about half of these. In addition to imprinting errors
in DMR1 and DMR2, other mechanisms may account for
BWS: (1) paternally derived duplications of chromosome
11p5.5 (these cases were the first to identify the BWS
locus); (2) paternal uniparental disomy for chromosome
11—invariably present in mosaic form—often associated
with neonatal hypoglycemia and hemi-hypertrophy, and
associated with the highest risk (about 25%) of embryonal
tumors, particularly Wilms tumor; and (3) maternally inher-
ited balanced translocations involving rearrangements of
11p15.

Russell–Silver Syndrome
This well-known condition has ‘opposite’ characteristics to
BWS by virtue of marked prenatal and postnatal growth
retardation. The head circumference is relatively normal,
the face rather small and triangular, giving rise to a ‘pseu-
dohydrocephalic’ appearance (Figure 7.28), and there may
be body asymmetry. About 10% of cases appear to be
due to maternal uniparental disomy, indicating that this
chromosome is subject to imprinting. In contrast to pater-
nally derived duplications of 11p15, which give rise to
overgrowth and BWS, maternally derived duplications FIGURE 7.28 Girl with Russell-Silver syndrome. Note the
of this region are associated with growth retardation. bossed forehead, triangular face, and ‘pseudohydrocephalic’
Recently it has been shown that about a third of appearance.
126 Patterns of Inheritance

I cardiomyopathy and conduction defects, diabetes, or deaf-

ness, have been characterized as being due to mutations in
mitochondrial genes (p. 181). Because mitochondria have
II
an important role in cellular metabolism through oxidative
phosphorylation, it is not surprising that the organs most
III susceptible to mitochondrial mutations are the central
FIGURE 7.29 Family tree consistent with mitochondrial nervous system, skeletal muscle and heart.
inheritance. In most persons, the mitochondrial DNA from different
mitochondria is identical, or shows what is termed homo-
plasmy. If a mutation occurs in the mitochondrial DNA of
an individual, initially there will be two populations of mito-
chondrial DNA, so-called heteroplasmy. The proportion of
Mitochondrial Inheritance mitochondria with a mutation in their DNA varies between
Each cell contains thousands of copies of mitochondrial cells and tissues, and this, together with mutational hetero-
DNA with more being found in cells that have high energy geneity, is a possible explanation for the range of phenotypic
requirements, such as brain and muscle. Mitochondria, and severity seen in persons affected with mitochondrial disor-
therefore their DNA, are inherited almost exclusively from ders (Figure 7.30).
the mother through the oocyte (p. 41). Mitochondrial DNA Whilst matrilineal inheritance applies to disorders that
has a higher rate of spontaneous mutation than nuclear are directly because of mutations in mitochondrial DNA, it
DNA, and the accumulation of mutations in mitochondrial is also important to be aware that mitochondrial proteins
DNA has been proposed as being responsible for some of are encoded mainly by nuclear genes. Mutations in these
the somatic effects seen with aging. genes can have a devastating impact on respiratory chain
In humans, cytoplasmic or mitochondrial inheritance has functions within mitochondria. Examples include genes
been proposed as a possible explanation for the pattern encoding proteins within the cytochrome c (COX) system,
of inheritance observed in some rare disorders that affect which follow autosomal recessive inheritance, and the G4.5
both males and females but are transmitted only through (TAZ) gene that is X-linked and causes Barth syndrome
females, so-called maternal or matrilineal inheritance (endocardial fibroelastosis) in males (p. 182). There is even
(Figure 7.29). a mitochondrial myopathy following autosomal dominant
A number of rare disorders with unusual combinations inheritance in which multiple mitochondrial DNA deletions
of neurological and myopathic features, sometimes can be detected. Further space is devoted to mitochondrial
occurring in association with other conditions such as disorders in Chapter 11 (p. 181).

Homoplasmy – no disease No disease No disease

Mild disease Severe disease

FIGURE 7.30 Progressive effects of heteroplasmy on the clinical severity of disease from mutations in the mitochondrial genome.
Low proportions of mutant mitochondria are tolerated well, but as the proportion increases different thresholds for cellular, and
hence tissue, dysfunction are breached (mauve circle represents the cell nucleus).
 Patterns of Inheritance 127

FURTHER READING Extensive review of examples of imprinting in inherited diseases in

humans.
Bateson W, Saunders ER 1902 Experimental studies in the physiology Heinig RM 2000 The monk in the garden: the lost and found genius
of heredity, pp 132–134. Royal Society Reports to the Evolution of Gregor Mendel. London: Houghton Mifflin
Committee, 1902 The life and work of Gregor Mendel as the history of the birth of
Early observations on mendelian inheritance. genetics.
Bennet RL, Steinhaus KA, Uhrich SB, et al 1995 Recommendations Kingston HM 1994 An ABC of clinical genetics, 2nd ed. London:
for standardized human pedigree nomenclature. Am J Hum Genet British Medical Association
56:745–752 A simple outline primer of the basic principles of clinical
Goriely A, McVean GAT, Rojmyr M, et al 2003 Evidence for selective genetics.
advantage of pathogenic FGFR2 mutations in the male germ line. Reik W, Surami A, eds 1997 Genomic imprinting (frontiers in molecu-
Science 301:643–646 lar biology). London: IRL Press
Hall JG 1988 Somatic mosaicism: observations related to clinical Detailed discussion of examples and mechanisms of genomic
genetics. Am J Hum Genet 43:355–363 imprinting.
Good review of findings arising from somatic mosaicism in clinical Vogel F, Motulsky AG 1996 Human genetics, 3rd ed. Berlin: Springer
genetics. This text has detailed explanations of many of the concepts in
Hall JG 1990 Genomic imprinting: review and relevance to human human genetics outlined in this chapter.
diseases. Am J Hum Genet 46:857–873

ELEMENTS
1 Family studies are often necessary to determine the mode of common an autosomal recessive allele, the greater the
inheritance of a trait or disorder and to give appropriate likelihood that the parents of a homozygote are
genetic counseling. A standard shorthand convention exists consanguineous.
for pedigree documentation of the family history.
5 X-linked recessive alleles are normally manifest only in males.
2 Mendelian, or single-gene, disorders can be inherited in five Offspring of females heterozygous for an X-linked recessive
ways: autosomal dominant, autosomal recessive, X-linked allele have a 1 in 2 chance of inheriting the allele from their
dominant, X-linked recessive, and, rarely, Y-linked inheritance. mother. Daughters of males with an X-linked recessive allele
are obligate heterozygotes but sons cannot inherit the allele.
3 Autosomal dominant alleles are manifest in the heterozygous
Rarely, females manifest an X-linked recessive trait because
state and are usually transmitted from one generation to the
they are homozygous for the allele, have a single X
next but can occasionally arise as a new mutation. They
chromosome, have a structural rearrangement of one of their
usually affect both males and females equally. Each offspring
X chromosomes, or are heterozygous but show skewed or
of a parent with an autosomal dominant gene has a 1 in 2
non-random X-inactivation.
chance of inheriting it from the affected parent. Autosomal
dominant alleles can exhibit reduced penetrance, variable 6 There are only a few disorders known to be inherited in an
expressivity, and sex limitation. X-linked dominant manner. In X-linked dominant disorders,
hemizygous males are usually more severely affected than
4 Autosomal recessive disorders are manifest only in the heterozygous females.
homozygous state and normally only affect individuals in
one generation, usually in one sibship in a family. They affect 7 Unusual features in single-gene patterns of inheritance can
both males and females equally. Offspring of parents who be explained by phenomena such as genetic heterogeneity,
are heterozygous for the same autosomal recessive allele have mosaicism, anticipation, imprinting, uniparental disomy, and
a 1 in 4 chance of being homozygous for that allele. The less mitochondrial inheritance.
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 CHAPTER 8

Population and
Mathematical
Genetics

In this chapter, some of the more mathematical aspects Do not worry about your difficulties
of gene inheritance are considered, together with how in mathematics. I can assure you mine
genes are distributed and maintained at particular frequen- are still greater.
cies in populations. This subject constitutes what is known
ALBERT EINSTEIN
as population genetics. Genetics lends itself to a numerical
approach, with many of the most influential and pioneering
figures in human genetics having come from a mathematical
background. They were particularly attracted by the chal-
lenges of trying to determine the frequencies of genes in
populations and the rates at which they mutate. Much of
The Hardy-Weinberg Principle
this early work impinges on the specialty of medical genet-
ics, and in particular on genetic counseling, and by the end Consider an ‘ideal’ population in which there is an auto-
of this chapter it is hoped that the reader will have gained somal locus with two alleles, A and a, that have frequencies
an understanding of the following. of p and q, respectively. These are the only alleles found at
1. Why a dominant trait does not increase in a population this locus, so that p + q = 100%, or 1. The frequency of
at the expense of a recessive one. each genotype in the population can be determined by
2. How the carrier frequency and mutation rate can be construction of a Punnett square, which shows how the
determined from the disease incidence. different genes can combine (Figure 8.1).
3. Why a particular genetic disorder can be more common From Figure 8.1, it can be seen that the frequencies of
in one population or community than another. the different genotypes are:
4. How it can be confirmed that a genetic disorder shows
Genotype Phenotype Frequency
a particular pattern of inheritance.
AA A p2
5. The concept of genetic linkage and how this differs from
Aa A 2pq
linkage disequilibrium.
Aa a q2
6. The effects of medical intervention.
If there is random mating of sperm and ova, the frequencies
of the different genotypes in the first generation will be as
Allele Frequencies in Populations shown. If these individuals mate with one another to
On first reflection, it would be reasonable to predict that produce a second generation, Punnett square can again be
dominant genes and traits in a population would tend to used to show the different matings and their frequencies
increase at the expense of recessive ones. On average, three- (Figure 8.2).
quarters of the offspring of two heterozygotes will manifest From Figure 8.2 the total frequency for each genotype
the dominant trait, but only one-quarter will have the reces- in the second generation can be derived (Table 8.1). This
sive trait. It might be thought, therefore, that eventually shows that the relative frequency or proportion of each
almost everyone in the population would have the dominant genotype is the same in the second generation as in the
trait. However, it can be shown that in a large randomly first. In fact, no matter how many generations are studied,
mating population, in which there is no disturbance by the relative frequencies will remain constant. The actual
outside influences, dominant traits do not increase at the numbers of individuals with each genotype will change as
expense of recessive ones. In fact, in such a population, the the population size increases or decreases, but their relative
relative proportions of the different genotypes (and pheno- frequencies or proportions remain constant. This is the
types) remain constant from one generation to another. This fundamental tenet of the Hardy-Weinberg principle.
is known as the Hardy-Weinberg principle, as it was pro- When studies confirm that the relative proportions of each
posed, independently, by an English mathematician, G. H. genotype remain constant with frequencies of p2, 2pq, and
Hardy, and a German physician, W. Weinberg, in 1908. This q2, then that population is said to be in Hardy-Weinberg
is a very important principle in human genetics. equilibrium for that particular genotype.
129
130 Population and Mathematical Genetics

Male gametes Genotype frequency of male

A a AA Aa aa
(p) (q) (p 2) (2pq) (q 2)

Genotype frequency of female parent

A AA Aa AA
Female gametes

p4 2p3q p2q2
(p) (p2) (pq) (p 2)

a Aa aa Aa
(q) (pq) (q2) (2pq) 2p3q 4p 2q 2 2pq3

FIGURE 8.1 Punnett square showing allele frequencies and

resulting genotype frequencies for a two-allele system in the first aa
(q 2) p2q2 2pq3 q4
generation.

FIGURE 8.2 Punnett square showing frequencies of the different

matings in the second generation.

Factors that Can Disturb

Hardy-Weinberg Equilibrium Assortative Mating
So far, this relates to an ‘ideal’ population. By definition This is the tendency for human beings to choose partners
such a population is large and shows random mating with who share characteristics such as height, intelligence, and
no new mutations and no selection for or against any par- racial origin. If assortative mating extends to conditions
ticular genotype. For some human characteristics, such as such as autosomal recessive (AR) deafness, which accounts
neutral genes for blood groups or enzyme variants, these for a large proportion of all congenital hearing loss, this will
criteria can be fulfilled. However, several factors can disturb lead to a small increase in the relative frequency of affected
Hardy-Weinberg equilibrium, either by influencing the dis- homozygotes.
tribution of genes in the population or by altering the gene
frequencies. These factors include:
Consanguinity
1. Non-random mating Consanguinity is the term used to describe marriage between
2. Mutation blood relatives who have at least one common ancestor no
3. Selection more remote than a great-great-grandparent. Widespread
4. Small population size consanguinity in a community will lead to a relative increase
5. Gene flow (migration). in the frequency of affected homozygotes but a relative
decrease in the frequency of heterozygotes.
Non-Random Mating
Random mating, or panmixis, refers to the selection of a
Mutation
partner regardless of that partner’s genotype. Non-random The validity of the Hardy-Weinberg principle is based on
mating can lead to an increase in the frequency of affected the assumption that no new mutations occur. If a particular
homozygotes by two mechanisms, either assortative mating locus shows a high mutation rate, then there will be a steady
or consanguinity. increase in the proportion of mutant alleles in a population.

Table 8.1 Frequency of the Various Types of Offspring from the Matings Shown in Figure 8.2
Frequency of Offspring
Mating Type Frequency AA Aa aa
4
AA × AA p4 p — —
AA × Aa 4p3q 2p3q 2p3q —
Aa × Aa 4p2q2 p2q2 2p2q2 p2q2
AA × aa 2p2q2 — 2p2q2 —
Aa × aa 4pq3 — 2pq3 2pq3
aa × aa q4 — — q4
Total p2(p2 + 2pq + q2) 2pq(p2 + 2pq + q2) q2(p2 + 2pq + q2)
Relative frequency p2 2pq q2
 Population and Mathematical Genetics 131

In practice, mutations do occur at almost all loci, albeit at Large population

different rates, but the effect of their introduction is usually 1.0
balanced by the loss of mutant alleles due to reduced fitness 'A' gene
of affected individuals. If a population is found to be in 0.8
Hardy-Weinberg equilibrium, it is generally assumed that
these two opposing factors have roughly equal effects.
0.6
This is discussed further in the section that follows on the
estimation of mutation rates.
0.4
Selection
In the ‘ideal’ population there is no selection for or against 0.2

Frequency of alleles
'a' gene
any particular genotype. In reality, for deleterious charac-
teristics there is likely to be negative selection, with affected 0
0 1 2 3 4 5 6
individuals having reduced reproductive (= biological =
‘genetic’) fitness. This implies that they do not have as many Small population
offspring as unaffected members of the population. In the 1.0 Fixation of
'A' gene
absence of new mutations, this reduction in fitness will lead
to a gradual reduction in the frequency of the mutant gene, 0.8
and hence disturbance of Hardy-Weinberg equilibrium.
Selection can act in the opposite direction by increasing
0.6
fitness. For some autosomal recessive disorders there is
evidence that heterozygotes show a slight increase in bio-
logical fitness compared with unaffected homozygotes— 0.4
referred to as heterozygote advantage. The best understood
example is sickle-cell disease, in which affected homozy- 0.2
gotes have severe anemia and often show persistent ill-
Extinction of
health (p. 159). However, heterozygotes are relatively 0 'a' gene
immune to infection with Plasmodium falciparum malaria 0 1 2 3 4 5 6
because their red blood cells undergo sickling and are rapidly Generations
destroyed when invaded by the parasite. In areas where this FIGURE 8.3 Possible effects of random genetic drift in large and
small populations.
form of malaria is endemic, carriers of sickle-cell anemia
(sickle cell trait), have a biological advantage compared with
unaffected homozygotes. Therefore, in these regions the
proportion of heterozygotes tends to increase relative to the
proportions of normal and affected homozygotes, and the gradient shown by the incidence of the B blood group
Hardy-Weinberg equilibrium is disturbed. allele throughout the world (Figure 8.4). This allele is
thought to have originated in Asia and spread slowly west-
Small Population Size ward as a result of admixture through invasion.
In a large population, the numbers of children produced by
Validity of Hardy-Weinberg Equilibrium
individuals with different genotypes, assuming no alteration
in fitness for any particular genotype, will tend to balance It is relatively simple to establish whether a population
out, so that gene frequencies remain stable. However, in a is in Hardy-Weinberg equilibrium for a particular trait if
small population it is possible that by random statistical all possible genotypes can be identified. Consider a system
fluctuation one allele could be transmitted to a high propor- with two alleles, A and a, with three resulting genotypes,
tion of offspring by chance, resulting in marked changes in AA, Aa/aA, and aa. Among 1000 individuals selected
allele frequency from one generation to the next, so that at random, the following genotype distributions are
Hardy-Weinberg equilibrium is disturbed. This is known as observed:
random genetic drift. If one allele is lost altogether, it is
AA 800
said to be extinguished and the other allele is described as
Aa/aA 185
having become fixed (Figure 8.3).
aa 15
Gene Flow (Migration) From these figures, the incidence of the A allele (p) equals
If new alleles are introduced into a population as a conse- [(2 × 800) + 185]/2000 = 0.8925 and the incidence of the
quence of migration, with later intermarriage, a change in a allele (q) equals [185 + (2 × 15)]/2000 = 0.1075.
the relevant allele frequencies will result. This slow diffu- Now consider what the expected genotype frequencies
sion of alleles across racial or geographical boundaries is would be if the population were in Hardy-Weinberg equi-
known as gene flow. The most widely quoted example is librium, and compare these with the observed values: