Disorders caused by a defect in a single gene follow the
patterns of inheritance described by Mendel and the term
mendelian inheritance has been used to denote unifactorial
inheritance since 1901. Individual disorders of this type are
often rare, but are important because they are numerous. By
2001, over 9000 established gene or phenotype loci were listed
in OMIM. Online Mendelian Inheritance in Man (TM).
McKusick-Nathans Institute for Genetic Medicine, Johns
Hopkins University (Baltimore, MD) and National Center for
Biotechnology Information, National Library of Medicine
(Bethesda, MD), 2000. World Wide Web URL:
http://www.ncbi.nlm.nih.gov/omim. Risks within an affected
family are often high and are calculated by knowing the mode
of inheritance and the structure of the family pedigree.
Saturday, April 11, 2009
Autosomal dominant disorders
Autosomal dominant disorders affect both males and females.
Mild or late onset conditions can often be traced through many
generations of a family. Affected people are heterozygous for
the abnormal allele and transmit this to half their offspring,
whether male or female. The disorder is not transmitted by
family members who are unaffected themselves. Estimation of
risk is therefore apparently simple, but in practice several
factors may cause difficulties in counselling families.
Mild or late onset conditions can often be traced through many
generations of a family. Affected people are heterozygous for
the abnormal allele and transmit this to half their offspring,
whether male or female. The disorder is not transmitted by
family members who are unaffected themselves. Estimation of
risk is therefore apparently simple, but in practice several
factors may cause difficulties in counselling families.
Late onset disorders
Dominant disorders may have a late or variable age of onset of
signs and symptoms. People who inherit the defective gene will
be destined to become affected, but may remain asymptomatic
well into adult life. Young adults at risk may not know whether
they have inherited the disorder and be at risk of transmitting
it to their children at the time they are planning their own
families. The possibility of detecting the mutant gene before
symptoms become apparent has important consequences for
conditions such as Huntington disease and myotonic dystrophy.
Predictive genetic testing is considered in chapter 3.
signs and symptoms. People who inherit the defective gene will
be destined to become affected, but may remain asymptomatic
well into adult life. Young adults at risk may not know whether
they have inherited the disorder and be at risk of transmitting
it to their children at the time they are planning their own
families. The possibility of detecting the mutant gene before
symptoms become apparent has important consequences for
conditions such as Huntington disease and myotonic dystrophy.
Predictive genetic testing is considered in chapter 3.
Variable expressivity
The severity of many autosomal dominant conditions varies
considerably between different affected individuals within the
same family, a phenomenon referred to as variable expressivity.
In some disorders this variability is due to instability of the
underlying mutation, as in the disorders caused by
trinucleotide repeat mutations (discussed in chapter 7). In
many cases, the variability is unexplained. The likely severity in
any affected individual is difficult to predict. A mildly affected
parent may have a severely affected child, as illustrated by
tuberous sclerosis, in which a parent with only skin
manifestations of the disorder may have an affected child with
infantile spasms and severe mental retardation. Tuberous
sclerosis also demonstrates pleiotropy, resulting in a variety of
apparently unrelated phenotypic features, such as skin
hypopigmentation, multiple hamartomas and learning
disability. Each of these pleiotropic effects can demonstrate
variable expressivity and penetrance in a given family.
considerably between different affected individuals within the
same family, a phenomenon referred to as variable expressivity.
In some disorders this variability is due to instability of the
underlying mutation, as in the disorders caused by
trinucleotide repeat mutations (discussed in chapter 7). In
many cases, the variability is unexplained. The likely severity in
any affected individual is difficult to predict. A mildly affected
parent may have a severely affected child, as illustrated by
tuberous sclerosis, in which a parent with only skin
manifestations of the disorder may have an affected child with
infantile spasms and severe mental retardation. Tuberous
sclerosis also demonstrates pleiotropy, resulting in a variety of
apparently unrelated phenotypic features, such as skin
hypopigmentation, multiple hamartomas and learning
disability. Each of these pleiotropic effects can demonstrate
variable expressivity and penetrance in a given family.
New mutations
New mutations may account for the presence of a dominant
disorder in a person who does not have a family history of the
disease. New mutations are common in some disorders, such as
achondroplasia, neurofibromatosis (NF1) and tuberous
sclerosis, and rare in others, such as Huntington disease and
myotonic dystrophy. When a disorder arises by new mutation,
the risk of recurrence in future pregnancies for the parents of
the affected child is very small. Care must be taken to exclude
mild manifestations of the condition in one or other parent
before giving this reassurance. This causes no problems in
conditions such as achondroplasia that show little variability,
but can be more difficult in many other conditions, such as
neurofibromatosis and tuberous sclerosis. It is also possible that
an apparently normal parent may carry a germline mutation.
In some cases the mutation will be confined to gonadal tissue,
with the parent being unaffected clinically. In others the
mutation will be present in some somatic cells as well. In
disorders with cutaneous manifestations, such as NF1, this may
lead to segmental or patchy involvement of the skin. In either
case, there will be a considerable risk of recurrence in future
children. A dominant disorder in a person with a negative
family history may alternatively indicate non-paternity.
disorder in a person who does not have a family history of the
disease. New mutations are common in some disorders, such as
achondroplasia, neurofibromatosis (NF1) and tuberous
sclerosis, and rare in others, such as Huntington disease and
myotonic dystrophy. When a disorder arises by new mutation,
the risk of recurrence in future pregnancies for the parents of
the affected child is very small. Care must be taken to exclude
mild manifestations of the condition in one or other parent
before giving this reassurance. This causes no problems in
conditions such as achondroplasia that show little variability,
but can be more difficult in many other conditions, such as
neurofibromatosis and tuberous sclerosis. It is also possible that
an apparently normal parent may carry a germline mutation.
In some cases the mutation will be confined to gonadal tissue,
with the parent being unaffected clinically. In others the
mutation will be present in some somatic cells as well. In
disorders with cutaneous manifestations, such as NF1, this may
lead to segmental or patchy involvement of the skin. In either
case, there will be a considerable risk of recurrence in future
children. A dominant disorder in a person with a negative
family history may alternatively indicate non-paternity.
Homozygosity
Homozygosity for dominant genes is uncommon, occurring
only when two people with the same disorder have children
together. This may happen preferentially with certain
conditions, such as achondroplasia. Homozygous
achondroplasia is a lethal condition and the risks to the
offspring of two affected parents are 25% for being an affected
homozygote (lethal), 50% for being an affected heterozygote,
and 25% for being an unaffected homozygote. Thus two out of
three surviving children will be affected.
only when two people with the same disorder have children
together. This may happen preferentially with certain
conditions, such as achondroplasia. Homozygous
achondroplasia is a lethal condition and the risks to the
offspring of two affected parents are 25% for being an affected
homozygote (lethal), 50% for being an affected heterozygote,
and 25% for being an unaffected homozygote. Thus two out of
three surviving children will be affected.
Autosomal recessive inheritance
Most mutations inactivate genes and act recessively. Autosomal
recessive disorders occur in individuals who are homozygous
for a particular recessive gene mutation, inherited from healthy
parents who carry the mutant gene in the heterozygous state.
The risk of recurrence for future offspring of such parents is
25%. Unlike autosomal dominant disorders there is usually no
preceding family history. Although the defective gene is passed
from generation to generation, the disorder appears only
within a single sibship, that is, within one group of brothers
and sisters. The offspring of an affected person must inherit
one copy of the mutant gene from them, but are unlikely to
inherit a similar mutant gene from the other parent unless the
gene is particularly prevalent in the population, or the parents
are consanguineous. In most cases, therefore, the offspring of
an affected person are not affected.
recessive disorders occur in individuals who are homozygous
for a particular recessive gene mutation, inherited from healthy
parents who carry the mutant gene in the heterozygous state.
The risk of recurrence for future offspring of such parents is
25%. Unlike autosomal dominant disorders there is usually no
preceding family history. Although the defective gene is passed
from generation to generation, the disorder appears only
within a single sibship, that is, within one group of brothers
and sisters. The offspring of an affected person must inherit
one copy of the mutant gene from them, but are unlikely to
inherit a similar mutant gene from the other parent unless the
gene is particularly prevalent in the population, or the parents
are consanguineous. In most cases, therefore, the offspring of
an affected person are not affected.
Autosomal recessive disorders
Autosomal recessive disorders are commonly severe, and
many of the recognised inborn errors of metabolism follow this
type of inheritance. Many complex malformation syndromes
are also due to autosomal recessive gene mutations and their
recognition is important in the first affected child in the family
because of the high recurrence risk. Prenatal diagnosis for
recessive disorders may be possible by performing biochemical
assays, DNA analysis, or looking for structural abnormalities in
the fetus by ultrasound scanning.
many of the recognised inborn errors of metabolism follow this
type of inheritance. Many complex malformation syndromes
are also due to autosomal recessive gene mutations and their
recognition is important in the first affected child in the family
because of the high recurrence risk. Prenatal diagnosis for
recessive disorders may be possible by performing biochemical
assays, DNA analysis, or looking for structural abnormalities in
the fetus by ultrasound scanning.
Common recessive genes
Worldwide, the haemoglobinopathies are the most common
autosomal recessive disorders. In certain populations, 1 in
6 people are carriers. In white populations 1 in 10 people carry
the C282Y haemochromatosis mutation. One in 400 people are
therefore homozygous for this mutation, although only one
third to one half have clinical signs owing to iron overload.
In northern Europeans the commonest autosomal recessive
disorder of childhood is cystic fibrosis. Approximately 1 in
25 of the population are carriers. In one couple out of every
625, both partners will be carriers, resulting in an incidence of
about 1 in 2500 for cystic fibrosis.
autosomal recessive disorders. In certain populations, 1 in
6 people are carriers. In white populations 1 in 10 people carry
the C282Y haemochromatosis mutation. One in 400 people are
therefore homozygous for this mutation, although only one
third to one half have clinical signs owing to iron overload.
In northern Europeans the commonest autosomal recessive
disorder of childhood is cystic fibrosis. Approximately 1 in
25 of the population are carriers. In one couple out of every
625, both partners will be carriers, resulting in an incidence of
about 1 in 2500 for cystic fibrosis.
Variability
Autosomal recessive disorders usually demonstrate full
penetrance and little clinical variability within families.
Haemochromatosis is unusual in that not all homozygotes
develop clinical disease. Women in particular are protected by
menstruation. In childhood onset SMA type I (Werdnig–Hoffman
disease) there is very little difference in the age at death between
affected siblings. However, the age at onset, severity and age at
death is more variable in intermediate SMA type II. Variation in
the severity of an autosomal recessive disorder between families is
generally explained by the specific mutation present in the gene.
In cystic fibrosis, delta F508 is the most common mutation and
most affected homozygotes have pancreatic insufficiency. Patients
with other particular mutations are more likely to be pancreatic
sufficient, may have less severe pulmonary disease if the
regulatory function of the gene is preserved, or even present
with just congenital absence of the vas deferens.
penetrance and little clinical variability within families.
Haemochromatosis is unusual in that not all homozygotes
develop clinical disease. Women in particular are protected by
menstruation. In childhood onset SMA type I (Werdnig–Hoffman
disease) there is very little difference in the age at death between
affected siblings. However, the age at onset, severity and age at
death is more variable in intermediate SMA type II. Variation in
the severity of an autosomal recessive disorder between families is
generally explained by the specific mutation present in the gene.
In cystic fibrosis, delta F508 is the most common mutation and
most affected homozygotes have pancreatic insufficiency. Patients
with other particular mutations are more likely to be pancreatic
sufficient, may have less severe pulmonary disease if the
regulatory function of the gene is preserved, or even present
with just congenital absence of the vas deferens.
New mutations
New mutations are rare in autosomal recessive disorders and it
can generally be assumed that both parents of an affected child
are carriers. New mutations have occasionally been documented
and occur in about 1% of SMA type I cases, where a child
inherits a mutation from one carrier parent with a new mutation
arising in the gene inherited from the other, non-carrier parent.
Recurrence risks for future siblings is therefore very low.
can generally be assumed that both parents of an affected child
are carriers. New mutations have occasionally been documented
and occur in about 1% of SMA type I cases, where a child
inherits a mutation from one carrier parent with a new mutation
arising in the gene inherited from the other, non-carrier parent.
Recurrence risks for future siblings is therefore very low.
Uniparental disomy
Occasionally, autosomal recessive disorders can arise through a
mechanism called uniparental disomy, in which a child inherits
two copies of a particular chromosome from one parent and
none from the other. If the chromosome inherited in this
uniparental fashion carries an autosomal recessive gene
mutation, then the child will be an affected homozygote.
Recurrence risk for future siblings is extremely low.
mechanism called uniparental disomy, in which a child inherits
two copies of a particular chromosome from one parent and
none from the other. If the chromosome inherited in this
uniparental fashion carries an autosomal recessive gene
mutation, then the child will be an affected homozygote.
Recurrence risk for future siblings is extremely low.
Genetic heterogeneity
Genetic heterogeneity is common and involves multiple alleles
at a single locus as well as multiple loci for some disorders.
Allelic heterogeneity implies that many different mutations can
occur in a disease gene. It is common for affected individuals to
have two different mutations in the disease-causing gene and
these people are referred to as compound heterozygotes. The
severity of the disorder may be influenced by the particular
combination of mutations present. Locus heterogeneity, where
a particular phenotype can be caused by different genes, is seen
in some autosomal recessive disorders. A number of recessive
genes at different loci cause severe congenital deafness and this
affects recurrence risk when two affected individuals have
children
at a single locus as well as multiple loci for some disorders.
Allelic heterogeneity implies that many different mutations can
occur in a disease gene. It is common for affected individuals to
have two different mutations in the disease-causing gene and
these people are referred to as compound heterozygotes. The
severity of the disorder may be influenced by the particular
combination of mutations present. Locus heterogeneity, where
a particular phenotype can be caused by different genes, is seen
in some autosomal recessive disorders. A number of recessive
genes at different loci cause severe congenital deafness and this
affects recurrence risk when two affected individuals have
children
Consanguinity
Consanguinity increases the risk of a recessive disorder because
both parents are more likely to carry the same defective gene,
that has been inherited from a common ancestor. The rarer the
condition the more likely it is to occur when the parents were
related before marriage. Overall, the increased risk of having a
child with severe abnormalities, including recessive disorders, is
about 3% above the risk in the general population.
both parents are more likely to carry the same defective gene,
that has been inherited from a common ancestor. The rarer the
condition the more likely it is to occur when the parents were
related before marriage. Overall, the increased risk of having a
child with severe abnormalities, including recessive disorders, is
about 3% above the risk in the general population.
X linked recessive inheritance
In X linked recessive conditions males are affected because
they have only a single copy of genes carried by the
X chromosome (hemizygosity), but the disorder can be
transmitted through healthy female carriers. A female carrier
of an X linked recessive disorder will transmit the condition to
half her sons, and half her daughters will be carriers. An
unaffected male does not transmit the disorder. An affected
male will transmit the mutant gene to all his daughters (who
must inherit his X chromosome), but to none of his sons (who
must inherit his Y chromosome). This absence of male to male
transmission is a hallmark of X linked inheritance. Many X
linked recessive disorders are severe or lethal during early life,
however, so that the affected males do not reproduce.
they have only a single copy of genes carried by the
X chromosome (hemizygosity), but the disorder can be
transmitted through healthy female carriers. A female carrier
of an X linked recessive disorder will transmit the condition to
half her sons, and half her daughters will be carriers. An
unaffected male does not transmit the disorder. An affected
male will transmit the mutant gene to all his daughters (who
must inherit his X chromosome), but to none of his sons (who
must inherit his Y chromosome). This absence of male to male
transmission is a hallmark of X linked inheritance. Many X
linked recessive disorders are severe or lethal during early life,
however, so that the affected males do not reproduce.
heterozygous femal
Occasionally a heterozygous female will show some features of the
condition and is referred to as a manifesting carrier. This is usually
due to non-random X inactivation leading to the chromosome
that carries the mutant allele remaining active in most cells. The
process of X inactivation that occurs in early embryogenesis is
normally random, so that most female carriers would have around
50% of the normal gene remaining active, which is sufficient to
prevent clinical signs. Alternatively, X chromosome abnormalities
such as Turner syndrome may give rise to X linked disorders in
females since, like males, they are hemizygous for genes carried by
the X chromosome. The homozygous affected state may occur in
females whose father is affected and whose mother is a carrier.
This is only likely to occur in common X linked disorders such as
red-green colour blindness, or glucose-6-phosphate
dehydrogenase deficiency in the Middle East.
condition and is referred to as a manifesting carrier. This is usually
due to non-random X inactivation leading to the chromosome
that carries the mutant allele remaining active in most cells. The
process of X inactivation that occurs in early embryogenesis is
normally random, so that most female carriers would have around
50% of the normal gene remaining active, which is sufficient to
prevent clinical signs. Alternatively, X chromosome abnormalities
such as Turner syndrome may give rise to X linked disorders in
females since, like males, they are hemizygous for genes carried by
the X chromosome. The homozygous affected state may occur in
females whose father is affected and whose mother is a carrier.
This is only likely to occur in common X linked disorders such as
red-green colour blindness, or glucose-6-phosphate
dehydrogenase deficiency in the Middle East.
Detecting carriers
Recognising X linked recessive inheritance is important because
many women in the family may be at risk of being carriers and
of having affected sons, irrespective of whom they marry.
Genetic assessment is important because of the high recurrence
risk and the severity of many X linked disorders. An X linked
recessive condition must be considered when the family history
indicates maternally related affected males in different
generations of the family. Family history is not always positive,
however, as new mutations are common, particularly in
conditions that are lethal in affected males. Identifying female
gene carriers requires interpretation of the family pedigree and
the results of specific carrier tests, including direct mutation
detection, DNA linkage studies or biochemical analysis.
many women in the family may be at risk of being carriers and
of having affected sons, irrespective of whom they marry.
Genetic assessment is important because of the high recurrence
risk and the severity of many X linked disorders. An X linked
recessive condition must be considered when the family history
indicates maternally related affected males in different
generations of the family. Family history is not always positive,
however, as new mutations are common, particularly in
conditions that are lethal in affected males. Identifying female
gene carriers requires interpretation of the family pedigree and
the results of specific carrier tests, including direct mutation
detection, DNA linkage studies or biochemical analysis.
X linked dominant gen
An X linked dominant gene will give rise to a disorder that
affects both hemizygous males and heterozygous females.
Although dominant, females may be less severely affected than
males, as in X linked hypophosphataemia (vitamin D-resistant
rickets) and oculomotor nystagmus, because of X inactivation
which results in expression of the mutant allele in only a
proportion of cells. The gene is transmitted through families in
the same way as X linked recessive genes: females transmit the
mutation to half their sons and half their daughters; males
transmit the mutation to all their daughters and none of their
sons. The pedigree, however, resembles autosomal dominant
inheritance except that there is no male to male transmission
and there is an excess of affected females. In some disorders the
condition appears to be lethal in affected males, for example
focal dermal hypoplasia (Goltz syndrome) and incontinentia
pigmenti. In these families there will be fewer males than
expected, half of the females will be affected and all surviving
males will be unaffected. An affected woman therefore has a
one in three chance of having an affected child and two thirds
of her children will be girls. Rett syndrome is a disorder that
affects girls almost exclusively and usually occurs sporadically,
since affected females do not reproduce. This disorder has been
shown to be due to a mutation in a gene located at Xq24,
confirming that it is an X linked dominant condition.
affects both hemizygous males and heterozygous females.
Although dominant, females may be less severely affected than
males, as in X linked hypophosphataemia (vitamin D-resistant
rickets) and oculomotor nystagmus, because of X inactivation
which results in expression of the mutant allele in only a
proportion of cells. The gene is transmitted through families in
the same way as X linked recessive genes: females transmit the
mutation to half their sons and half their daughters; males
transmit the mutation to all their daughters and none of their
sons. The pedigree, however, resembles autosomal dominant
inheritance except that there is no male to male transmission
and there is an excess of affected females. In some disorders the
condition appears to be lethal in affected males, for example
focal dermal hypoplasia (Goltz syndrome) and incontinentia
pigmenti. In these families there will be fewer males than
expected, half of the females will be affected and all surviving
males will be unaffected. An affected woman therefore has a
one in three chance of having an affected child and two thirds
of her children will be girls. Rett syndrome is a disorder that
affects girls almost exclusively and usually occurs sporadically,
since affected females do not reproduce. This disorder has been
shown to be due to a mutation in a gene located at Xq24,
confirming that it is an X linked dominant condition.
Y linked inheritance
In Y linked inheritance, only males would be affected, with
transmission being from a father to all his sons via the
Y chromosome. This pattern of inheritance has previously been
suggested for such conditions as porcupine skin, hairy ears,
and webbed toes. In most conditions in which Y linked
inheritance has been postulated the actual mode of inheritance
is probably autosomal dominant with sex limitation. Genes
involved in male development and spermatogenesis are carried
by the Y chromosome, but the mode of inheritance is not
demonstrated because of the associated infertility.
transmission being from a father to all his sons via the
Y chromosome. This pattern of inheritance has previously been
suggested for such conditions as porcupine skin, hairy ears,
and webbed toes. In most conditions in which Y linked
inheritance has been postulated the actual mode of inheritance
is probably autosomal dominant with sex limitation. Genes
involved in male development and spermatogenesis are carried
by the Y chromosome, but the mode of inheritance is not
demonstrated because of the associated infertility.
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