Download Patterns of Inheritance

Patterns of Inheritance
- Chromosomal Patterns of Inheritance
It is important to clarify at the outset the difference between chromosome abnormalities and
single gene disorders. Chromosome abnormalities are errors that result in an abnormal
chromosome number or an abnormal chromosome structure. These abnormalities lead to the
loss or gain of chromosome material. All the genes within these chromosomes, however, are
normal. Most chromosome abnormalities are sporadic with a small to negligible risk of
recurrence. Of those that are familial, the risk of recurrence is usually less than 15%.
In the case of single gene disorders, the error lies in a mutation or change within the DNA
sequence. Errors that occur within a gene can result in absent, deficient or abnormal protein
products. The chromosomes, or karyotype, of a patient with a single gene disorder are
expected to be normal, 46,XX or 46,XY. Therefore, chromosome studies are not
recommended for patients who are thought to have a single gene disorder such as cystic
fibrosis or muscular dystrophy.
- Mendelian Patterns of Inheritance
Mendelian genetic disorders are disorders caused by a single gene mutation that leads to an
abnormality that is usually confined to an organ system (e.g., skeletal as in achondroplasia,
CNS as in Huntington disease). The units of heredity, or genes, are DNA sequences that code
for the synthesis of proteins. Genes are submicroscopic segments of DNA and cannot be
detected by chromosome analysis. Like chromosomes, genes are inherited in pairs, one from
each parent.
A gene may be altered by an event that causes a change in the nucleotide bases, a mutation.
The different forms of a gene are called alleles (e.g., the gene for eye color has blue, brown,
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hazel, etc. alleles). If the pair of alleles is alike, the individual is said to be homozygous. If
the pair of alleles is different, the individual is said to be heterozygous.
There are approximately 25,000 genes on the 23 pairs of chromosomes. It is estimated that
every individual has several altered genes. In most cases these altered genes are recessive and
the normal dominant allele results in expression of the normal trait. There are thousands of
different single gene disorders. If a condition is due to an alteration in a gene on an autosomal
chromosome (1 through 22), it is inherited in an autosomal dominant or autosomal
recessive fashion. If the altered gene is located on the X chromosome, it is inherited in an Xlinked fashion.
For a dominant trait to be expressed, one dominant gene will suffice. A gene mutation
behaves in a dominant manner if it acquires a new or different function that is
disadvantageous (or advantageous) to the cell. In effect, the mutation results in a "gain of
function."
For a recessive trait to be observed, however, two recessive genes must be present. A gene
mutation behaves in a recessive manner if it produces a non-functional protein. If a cell
contains at least one gene that codes for normal protein production, the presence of the
recessive gene will be masked. When a cell has two recessive genes and is not able to
produce a functional protein, then the recessive trait will be expressed. In effect, the mutation
results in "loss of function."
- Autosomal Recessive Inheritance
The concept of one gene, one enzyme was introduced by Beadle and Tatum. This resulted in
the identification of numerous inborn errors of metabolism, most of which are recessive
traits.
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A classic example of an autosomal recessive inborn error of metabolism is phenylketonuria
(PKU). PKU is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAM)
produced in the liver. The deficiency of PAH results in accumulation of phenylalanine and
metabolites such as phenylpyruvic acid in the blood and cerebrospinal fluid. Patients are
relatively healthy and survive into adult life. However, without treatment there is significant
brain damage with severe to profound mental retardation.
On occasion there are PKU patients who do not respond to dietary control and continue to
have elevated blood phenylalanine levels with associated seizures and progressive mental
retardation. This variant of PKU is the result of another gene mutation. In these patients, the
PAH gene is normal. The problem is caused by a mutation in a gene involved in the synthesis
of tetrahydrobiopterin, a co-factor of phenylalanine hydroxylase. This is an example of locus
heterogeneity (allele heterogeneity). In this example, PKU can be caused by abnormalities
in two different genes at two different sites or loci on the chromosomes.
Mutations can occur anywhere along the length of the gene, affecting introns, exons or the
immediate flanking regions. These mutations can affect the amount of protein or enzyme that
is produced or the protein or enzyme function. Mutations within a gene can result in the
following:

The gene can be completely deleted resulting in the absence of the protein.

There can be a partial deletion of the gene resulting in the formation of an abbreviated
protein.

The mutation may affect the enzyme's active site and reduce or abolish catalytic
activity.

The mutation may affect the stability of the enzyme so that it is degraded more
rapidly.

There can be an abnormality of the immediate flanking region affecting messenger
RNA transcription and, therefore, protein synthesis.
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Individuals with one normal gene and one mutated gene are often unaffected, suggesting that
the enzyme product of one normal gene is sufficient to supply the needs of an individual.
This is why biochemical assays often show 50% enzymatic function among carriers when
compared with non-carriers.
- Autosomal Dominant Inheritance
In conditions that are inherited in an autosomal dominant fashion, affected individuals are
heterozygous for an autosomal dominant disease gene and a normal gene. In such cases, the
presence of the abnormal gene results in the clinical expression of a disease or a condition.
Roughly, there are four times more dominant traits than recessive traits recognized in
humans. This is because a recessive trait can be carried through generations "hidden" from
view. A dominant trait is invariably expressed in the phenotype. All individuals with a
dominant trait must carry the abnormal gene with a 50% chance that they will pass this gene
on to their offspring. An example is Huntington disease (HD) where individuals with the
abnormal gene will invariably develop clinical signs and symptoms.
There are, however, several variations to this relatively simple inheritance pattern. It is not
uncommon to find pedigrees where an index case has an autosomal dominant trait and clearly
normal parents.
New (de novo) mutation refers to a DNA change that transforms the gene from normal to
abnormal in the egg or sperm that forms the zygote. Realize that the other germ cells of the
parent are usually unaffected or normal and the risk of recurrence in future offspring is
virtually the same as the general population. The affected individual, however, will have a
50% risk of having affected offspring. A good example is achondroplasia. Eight out of 10
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cases of achondroplasia are secondary to new mutations. Only two out of 10 individuals with
achondroplasia have a similarly affected parent.
On occasion, two or more sibs with an autosomal dominant trait have normal parents. This
can be explained on the basis of germline or gonadal mosaicism. Conceivably, early in
development, an individual could have a mutation that is limited to the germline (germ cells egg or sperm) while sparing the somatic cells. Such individuals are phenotypically normal;
however, they have a greater risk of recurrence than the general population. This
phenomenon has been described in osteogenesis imperfecta, achondroplasia and Duchenne
muscular dystrophy.
Finally, an affected child with normal parents can be explained on the basis of incomplete
penetrance. The premise in autosomal dominant inheritance is that an individual who carries
an abnormal gene will have an observable abnormal phenotype, however, there are
exceptions. On occasion, a person who carries an autosomal dominant gene may be
physically normal. For autosomal dominant traits, the term "penetrance" refers to the
number of gene carriers who are affected, divided by the total number of gene carriers who
are affected and unaffected. Thus, a gene can have an 80% penetrance rate (80 affected
people among 100 with the gene).
The non-penetrant carrier is a loose term used to describe an individual who carries the
abnormal gene, but does not express the disease or the trait. About 20% of individuals who
carry the gene for retinoblastoma (Rb) are nonpenetrant carriers. This lack of penetrance can
be explained as follows:
Variable expressivity refers to the severity of the disease or trait: mild, moderate, or severe.
Very often, variable penetrance and expressivity are used synonymously. Penetrance is an
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all or none phenomenon - either the abnormal phenotype is present or it is absent. If the
phenotype is absent, then it is nonpenetrant. If the phenotype is apparent, then it is penetrant
and can have variable expressivity.
The explanations for variable expressivity of a gene include:

The presence of modifier genes, (i.e., other genes within an individual's genome can
interact with the abnormal gene to either increase or decrease its expression.

Heterogeneity, as previously discussed in recessive inheritance, can affect expression. A
particular disease phenotype could be due to mutations in several different genes from
different loci (locus heterogeneity) or it could be due to different mutations within one
gene (allele heterogeneity), both causing different degrees of clinical severity.

Environmental factors can ameliorate or aggravate the disease process.

Another explanation is pleiotrism. Pleiotropism refers to the multiple effects of a gene in
different tissues or organs. Autosomal dominant traits are commonly pleiotropic. The
diagnosis of Marfan syndrome is made based a triad of cardiovascular (aortic
aneurysm, aortic insufficiency), skeletal (long limbs, fingers and toes, loose-jointedness),
and eye (dislocated lens) findings. Although several organ systems are involved, the basic
defect is an abnormality in the fibrillin protein, which is found in connective tissue.
Multi-organ system involvement is also seen in such conditions as osteogenesis
imperfecta (bones, teeth, sclera of the eye).
In autosomal dominant traits with complete penetrance, the chance that an affected person
will have an affected child is 50%, providing the affected individual has an unaffected
partner. There is also a 50% chance that the affected individual will have an unaffected child.
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- X-Linked Inheritance
Diseases caused by genes on the X-chromosome are said to be X-linked. Most X-linked
diseases are recessive, but a few are X-linked dominant. In contrast to the X chromosome, the
Y-chromosome is mostly inactive heterochromatin with a small active portion coding for the
testis-determining factor.
Females have two X chromosomes and males have only one. In the XX female, one X
chromosome in each cell becomes genetically inactive at an early stage in embryogenesis.
The inactive X becomes a Barr body. The inactivation of the X chromosome is random.
Generally, maternally and paternally derived X chromosomes are inactivated in equal
numbers. Therefore, females produce X-linked gene products (e.g., factor VIII protein in
hemophilia, creatine phosphokinase enzyme in Duchenne muscular dystrophy) in quantities
roughly similar to males (dosage compensation).
Because males have only one X chromosome (hemizygous), the presence of an abnormal
gene on the X chromosome is invariably expressed. However, in females who have two X
chromosomes, the presence of one abnormal recessive gene is usually compensated by the
presence of a normal gene on the other X chromosome (heterozygous). For this reason, Xlinked conditions like hemophilia or muscular dystrophy are expressed in sons and
transmitted by physically normal carrier mothers.
The concept of dominance and recessiveness is not particularly relevant in X-linked
inheritance. Whether dominant or recessive, an abnormal gene on the X chromosome in
males is invariably expressed. A recessive gene in a carrier female is occasionally expressed
due to the inactivation of a significant number of the X chromosomes containing the normal
gene. By the same token, a dominant trait in a carrier female can escape expression because
of inactivation of a majority of the X chromosomes with the abnormal gene.
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Since the X chromosome inactivation is random, it is just as likely that either the normal X or
the abnormal X is inactivated. At the gene level, the cell either does or does not produce a
gene product. Since an organ (e.g., the liver) originates from a small cluster of cells, by
chance alone, a large number of the cells within the organ could have a normal functioning X
(or an abnormal functioning X). Thus, X chromosome inactivation, or lyonization, creates
normal cells and abnormal cells depending on whether the normal X or the abnormal X is
active, on average, 50% of each. The extreme, however, is possible. While unlikely, it is
possible that X chromosome inactivation will result in the formation of 90% abnormal cells
and 10% normal cells. There are well-documented reports of female hemophilia carriers
who produce very low levels of factor VIII and for practical purposes can be considered mild
hemophiliacs. Thus lyonization can modify the expression of abnormal genes, whether
dominant or recessive, on the X chromosomes in females.
In most cases women who carry X-linked recessive disease genes are physically normal.
There is a 50% chance with each pregnancy that a carrier female will pass on the abnormal
recessive gene. With a Y-chromosome from her partner, she will have an affected son. With
an X-chromosome from her partner, she will have a carrier daughter. There is also a 50%
chance that a carrier female will pass on the normal X gene. If this is the case, her son will
not be affected and her daughter will not be a carrier. Affected males have normal offspring.
Their sons, receiving the Y, are free of the trait. Their daughters, receiving the abnormal X,
are obligate carriers.
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- Non-traditional (Non-Mendelian) Patterns of Inheritance
The rules set by Mendel have survived the test of time. Concepts of autosomal dominant,
autosomal recessive, and X-linked genetic patterns of transmission remain valid. However,
numerous inconsistencies have been observed, and the recent discoveries provide insight into
the genetic basis of some of these concepts.
1- Mosaicism
Mosaicism refers to the presence of two or more distinct cell lines, one normal and one
abnormal. This was first recognized in chromosomal disorders. Fifty percent of women with
Turner syndrome, for instance, have 45,X in all of their cells. The other 50% have
mosaicism, with chromosomally normal cells and abnormal cells in varying proportions.
Conditions associated with hemihypertrophy or hemihyperplasia, where one side of the body
is bigger than the other side, have also been shown to be caused by chromosomal mosaicism.
2- Imprinting
Imprinting refers to modification of the gene as it is transmitted through the father or the
mother. In mice studies, imprinting is well recognized, probably as a mechanism to guard
against parthenogenesis (self-fertilization). Using pronucleus transplantation, mouse zygotes
can be constructed containing both paternal (sperm) pronuclei, or both maternal (egg)
pronuclei. With both paternal pronuclei, a relatively well developed placenta, but poorly
developed embryo, results. With both maternal pronuclei, an embryo develops with a very
small placenta leading to early loss. The human counterpart is ovarian teratoma or dermoid
tumors when the two sets of chromosomes are maternal in origin, or a hydatidiform mole
when the two sets of chromosomes in the fertilized egg are paternal in origin.
Prader-Willi (PWS) and Angelman (AS) syndromes exemplify the concept of imprinting.
Both conditions are due to a deletion of the same chromosomal segment, 15q11-12. If the
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deleted chromosome 15 is paternal in origin, the patient will have PWS. If the deleted
chromosome is maternal in origin, the patient will have AS. For the deletion to have a
different clinical effect, when transmitted from the father or the mother, suggests that there
must be some modification of the chromosome segment that occurs as it passes through
paternal or maternal meiosis.
3- Uniparental Disomy
Uniparental disomy (UPD) refers to a pair of chromosomes being inherited from one parent.
Uniparental isodisomy refers to both chromosomes coming from one parent carrying
identical genes (from one grandparent). Uniparental heterodisomy refers to a pair of
chromosomes coming from one parent but carrying different genes (from both grandparents).
About 20-30% of individuals with PWS show no deletion on chromosome analysis, FISH or
DNA studies. In these instances, both number 15 chromosomes are of maternal origin, i.e., no
paternal contribution. This makes it analogous to PWS, which occurs, secondary to a paternal
deletion of 15q11. The maternal uniparental disomy (and, therefore, the absence of a
paternally imprinted chromosome 15) creates clinical features of Prader-Willi syndrome.
Uniparental disomy is presumed to occur in a zygote that, at conception, had three copies of
chromosome 15. These trisomic conditions are ordinarily not compatible with life. Survival
of the embryo occurs following the random loss of the third chromosome with resulting UPD.
4- Triplet Repeats
A number of conditions have been associated with triplet repeats (3 DNA bases), a feature
normally present in the genome. The three bases (e.g., CAG, CTG or CGG) are repeated
sequentially and are of varying lengths in normal individuals. However, the number of triplet
sequences increases above the expected range in individuals with certain genetic conditions.
These triplet repeats are found close to the beginning, within, or close to the end of a gene.
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The function of these repeated DNA sequences is not clearly defined. As the triplet repeat is
passed on to subsequent generations, it can undergo expansion in size and result in earlier
onset (anticipation) or more severe disease in the offspring.
1- Fragile X syndrome is associated with CGG repeats. Among normal individuals, the
number of CGG repeats is between 6 and 40. Unaffected carriers, who carry a premutation,
have between 50-200 copies of the CGG repeats. Affected individuals with the full mutation,
have over 200-1,000 CGG repeats.
2- Huntington disease (HD), associated with CAG repeats, is an adult onset
neurodegenerative condition affecting mainly the basal ganglia. Persons with HD develop a
movement disorder (choreoathetoid or dance-like movement) and dementia. Their life span,
on average, is 15 years after the onset of symptoms. The number of triplet repeats in normal
individuals is 11-34. Individuals with HD have 39 repeats or more. Those with repeats in the
60 70 range have a juvenile onset HD. Most individuals with juvenile expression of HD
inherit the gene from their father, following an expansion of the triplet repeat, which is more
likely to occur in male meiosis.
3- Myotonic dystrophy is associated with an increase in the number of CTG repeats.
Myotonia refers to the inability to relax following muscle contraction, (i.e., opening a
clenched hand or extending a flexed elbow). Often, there is associated frontal balding,
testicular atrophy, and subsequent weakness. Considered a dominant trait, both males and
females are affected. The normal number of CTG repeats is 5-30. There is a gray zone of 3070 repeats where there is potential for expansion during meiosis. Affected individuals have
more than 70 repeats. The peculiarity of this condition is the occurrence of congenital
myotonic dystrophy among newborns inheriting the condition from the mother, a
phenomenon not observed when the condition is inherited from the father.
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5- Contiguous Gene Syndromes
Contiguous gene syndromes are conditions that occur secondary to microdeletions or
microduplications involving several neighbouring genes. The occurrence of mental
retardation in individuals with syndromes normally associated with normal psychomotor
development (the gene for neurofibromatosis was discovered on 7q because a chromosome
abnormality was seen in a mentally retarded person with NF), or the association of ordinarily
distinct entities (Di-George syndrome and velo-cardio-facial syndrome on 22q), should
trigger a request for a high resolution chromosome study and/or FISH or molecular DNA
studies to rule out a microdeletion or microduplication. Examples of contiguous gene
syndromes are: cri-du-chat, Wolf-Hirschhorn syndrome, , retinoblastoma, Miller-Dieker
syndrome, DiGeorge syndrome, velo-cardio-facial syndrome, and Smith-Magenis syndrome.
6- Mitochondrial Inheritance
There are a few rare conditions due to abnormalities of mitochondrial DNA (mtDNA).
Mitochondria are organelles in the cytoplasm that provide energy for cellular metabolism
through a process called oxidative phosphorylation. There are several hundred mitochondria
per cell, which replicate independent of the nucleus. Mitochondrial inheritance is
characterized by great variability depending on the number of abnormal versus normal
mitochondria within the cell. Since the mitochondria are inherited from the cytoplasm of
the egg, it has a vertical mode of inheritance. Mitochondrial DNA abnormalities can affect
both males and females; however, they are inherited solely from the mother. Examples of
mitochondrial DNA abnormalities include: LHON - Leber hereditary optic neuropathy;
MELAS - mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes; and
MERRF - myoclonic epilepsy with ragged red fibers.
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7- Multifactorial Inheritance
The most common cause of genetic disorders is multifactorial or polygenic inheritance. Traits
that are due to the combined effects of multiple genes are polygenic (many genes). When
environmental factors also play a role in the development of a trait, the term multifactorial is
used to refer to the additive effects of many genetic and environmental factors. Expression of
these traits may follow a normal, or "bell-shaped," curve. Examples of multifactorial traits
include cleft lip and palate, congenital hip dislocation, schizophrenia, diabetes and neural
tube defects such as spine bifida.
Multifactorial conditions tend to run in families, but the pattern of inheritance is not as
predictable as with single gene disorders. The chance of recurrence is also less than the risk
for single gene disorders. The degree of risk of a multifactorial disorder occurring in relatives
is related to the number of genes they share in common with the affected individual. The
closer the degree of relationship, the more genes in common. The degree of risk also
increases with the degree of severity of the disorder.
Although multifactorial conditions run in families, the risk is generally less than the 25% or
50% seen in Mendelian conditions. Identical twins, who are exactly alike genetically, do not
always have the same condition when inheritance is multifactorial. This indicates that there
are non-genetic factors that also play a role in the expression of multifactorial traits. For
instance, the risk of coronary heart disease increases with smoking or obesity. The risk of
emphysema in individuals with alpha-1-antitrypsin deficiency increases greatly with
smoking. Maternal ingestion of valproic acid increases the risk of spine bifida. Maternal
alcohol abuse or uncontrolled diabetes increases the risk of having a child with a congenital
heart defect. Empiric risks are used to predict the recurrence of a multifactorial disorder. This
is a risk that is based on epidemiologic and population studies and on mathematical models.
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