CHROMOSOMAL ANOMALIES

A genetic disorder is an illness caused by one or more abnormalities in the

genome, especially a condition that is present from birth (congenital). Most genetic
disorders are quite rare and affect one person in every several thousands or millions.
Genetic disorders may or may not be heritable, i.e., passed down from the parents'
genes. In non-heritable genetic disorders, defects may be caused by new mutations
or changes to the DNA. In such cases, the defect will only be heritable if it occurs in
the germ line. The same disease, such as some forms of cancer, may be caused by
an inherited genetic condition in some people, by new mutations in other people, and
mainly by environmental causes in still other people. Whether, when and to what
extent a person with the genetic defect or abnormality will actually suffer from the
disease is almost always affected by environmental factors and events in the
person's development. Chromosome abnormalities usually occur when there is
an error in cell division. Most chromosome abnormalities occur as an accident
in the egg or sperm. Therefore, the abnormality is present in every cell of the
body. Some abnormalities, however, can happen after conception, resulting in
mosaicism, where some cells have the abnormality and some do not.
• Chromosome abnormalities can be inherited from a parent
(such as a translocation) or be "de novo" (new to the
individual). This is why chromosome studies are often
performed on parents when a child is found to have an
abnormality.The factors that can increase the risk of
chromosome abnormalities are:
• Maternal Age: Women are born with all the eggs they will ever
have. Therefore, when a woman is 30 years old, so are her
eggs. Some researchers believe that errors can crop up in the
eggs' genetic material as they age over time. Therefore, older
women are more at risk of giving birth to babies with
chromosome abnormalities than younger women. Since men
produce new sperm throughout their life, paternal age does
not increase risk of chromosome abnormalities.
Environment: Although there is no conclusive evidence that
specific environmental factors cause chromosome
abnormalities, it is still a possibility that the environment may
• Chromosomal abnormalities can be numerical or
structural
• Numerical :This is called aneuploidy (an abnormal
number of chromosomes), and occurs when an
individual either is missing a chromosome from a pair
(monosomy) or has more than two chromosomes of a
pair (trisomy, tetrasomy, etc.).
• In humans, an example of a condition caused by a
numerical anomaly is Down Syndrome, also known as
Trisomy 21 (an individual with Down Syndrome has three
copies of chromosome 21, rather than two). Trisomy has
been determined to be a function of maternal age. An
example of monosomy is Turner Syndrome, where the
individual is born with only one sex chromosome, an X.
• Structural anomaly can take several forms:
• Deletions: A portion of the chromosome is missing or deleted. Known
disorders in humans include Wolf-Hirschhorn syndrome, which is
caused by partial deletion of the short arm of chromosome 4; and
Jacobsen syndrome, also called the terminal 11q deletion disorder.
• Duplications: A portion of the chromosome is duplicated, resulting in
extra genetic material. Known human disorders include Charcot-
Marie-Tooth disease type 1A, which may be caused by duplication of
the gene encoding peripheral myelin protein 22 (PMP22) on
chromosome 17.
• Translocations: A portion of one chromosome is transferred to
another chromosome. There are two main types of translocations:
• Reciprocal translocation: Segments from two different chromosomes
have been exchanged.
• Robertsonian translocation: An entire chromosome has attached to
another at the centromere - in humans these only occur with
chromosomes 13, 14, 15, 21, and 22.
• Inversions: A portion of the chromosome has broken off, turned
upside down, and reattached, therefore the genetic material is
inverted.
• Insertions: A portion of one chromosome has been deleted from its
normal place and inserted into another chromosome.
• Rings: A portion of a chromosome has broken off and formed a circle
or ring. This can happen with or without loss of genetic material.
• Isochromosome: Formed by the mirror image copy of a chromosome
segment including the centromere.
• Chromosome instability syndromes are a group of disorders
characterized by chromosomal instability and breakage. They often
lead to an increased tendency to develop certain types of
malignancies.
• Most chromosome abnormalities occur as an accident in the egg or
sperm, and therefore the anomaly is present in every cell of the body.
Some anomalies, however, can happen after conception, resulting in
Mosaicism (where some cells have the anomaly and some do not).
Chromosome anomalies can be inherited from a parent or be "de
 Chromosomal Anomalies
• Chromosome structural anomalies

Translocation Deletion Inversion Isochromosome

Insertion Ring
Derivative
chromosome chromosome
• The majority of human chromosomal
abnormalities occur in the autosomes. Most of
these abnormalities are monosomies or
trisomies. All fetuses with autosomal
monosomies spontaneously abort early in
pregnancy. Likewise, almost all fetuses with
autosomal trisomies die before birth. Those that
survive usually have multiple physical
malformations, mental retardation, and relatively
short lives.
• Autosomal Dominant, Multifactorial Chromosomal
Abnormalities
• Another category of hereditary disease is called
autosomal dominant disease- Because the defective gene
is dominant, the disease is expressed even if only one
gene is defective. A normal gene cannot mask the
harmful effects of an abnormal gene as it can in
autosomal recessive disease. If one parent has an
autosomal dominant disease, the chances are 50 percent
that each child will inherit the disorder.
• Huntington chorea: An example of an autosomal
dominant disease is Huntington chorea, a brain disease
marked by abnormal body movements and mental
deterioration beginning in middle age.
 Autosomal Recessive Disease

• Two copies of the gene must be mutated for a

person to be affected by an autosomal recessive
disorder. An affected person usually has unaffected
parents who each carry a single copy of the mutated
gene (and are referred to as carriers). Two
unaffected people whom each carry one copy of the
mutated gene have a 25% chance with each
pregnancy of having a child affected by the disorder.
Examples of this type of disorder are
Medium-chain acyl-CoA dehydrogenase deficiency ,
cystic fibrosis, sickle-cell disease, Tay-Sachs disease,
Roberts syndrome.
• X-linked dominant
• X-linked dominant disorders are caused by mutations in
genes on the X chromosome. Only a few disorders have
this inheritance pattern, with a prime example being
X-linked hypophosphatemic rickets. Males and females
are both affected in these disorders, with males typically
being more severely affected than females. Some X-linked
dominant conditions, such as Rett syndrome, usually fatal
in males either in utero or shortly after birth, and are
therefore predominantly seen in females. Exceptions to
this finding are extremely rare cases in which boys with
Klinefelter syndrome (47,XXY) also inherit an X-linked
dominant condition and exhibit symptoms more similar to
those of a female in terms of disease severity.
• X-linked recessive
• X-linked recessive conditions are also caused by mutations
in genes on the X chromosome. Males are more frequently
affected than females, and the chance of passing on the
disorder differs between men and women. The sons of a
man with an X-linked recessive disorder will not be
affected, and his daughters will carry one copy of the
mutated gene. A woman who is a carrier of an X-linked
recessive disorder (XRXr) has a 50% chance of having sons
who are affected and a 50% chance of having daughters
who carry one copy of the mutated gene and are therefore
carriers. X-linked recessive conditions include the serious
diseases hemophilia A, Duchenne muscular dystrophy,
male pattern baldness , color blindness.
 Y linked Disorders

• Y-linked disorders, also called holandric disorders, are caused by

mutations on the Y chromosome. These conditions display may only be
transmitted from the heterogametic sex (e.g. male humans) to offspring
of the same sex. More simply, this means that Y-linked disorders in
humans can only be passed from men to their sons; females can never
be affected because they do not possess Y allosomes.
• Y-linked disorders are exceedingly rare but the most well-known
examples typically cause infertility. Reproduction in such conditions is
only possible through the circumvention of infertility by medical
intervention.
• Mitochondrial disease
• This type of inheritance, also known as maternal inheritance, applies to
genes in mitochondrial DNA. Because only egg cells contribute
mitochondria to the developing embryo, only mothers can pass on
mitochondrial conditions to their children. An example of this type of
disorder is Leber's hereditary optic neuropathy.
• Multifactorial genetic diseases are illnesses that
tend to run in families. These diseases are not
due simply to the inheritance of a single
defective gene. Rather, a cluster of faulty genes
is inherited, which predisposes the person to a
disease. Given the appropriate environmental
factors, the person may actually develop that
disease. Examples of illnesses that run in
families include such chronic adult diseases as
coronary heart disease, high blood pressure,
and stomach ulcers, as well as birth defects,
such as cleft lip and palate and spina bifida.
 Autosomal anomalies

• The most well known and common autosomal

abnormality is
• Down syndrome: The cause of 21 trisomy is meiotic
nondisjunction. People with Down syndrome have an
irregularity with autosome pair 21. In most cases, there
is an extra chromosome (i.e., trisomy 21). More rarely
(3-5%), there is a structural modification in this
chromosome. Specifically, there is a translocation of all
or part of chromosome 21 to chromosome 14 or 15. It is
thought that there are at least 350 genes involved.
About 2-4% of the people with Down syndrome are
genetically mosaic. Women above 35yrs are at Risk of
having children with Down syndrome
• People with Down syndrome typically have short, stocky
bodies with thick hands and feet. Their hands also
commonly have a "simian crease", which is a crease in the
palm that runs completely from one side of the hand to the
other. In addition, they typically have broad, short heads
with small low-set ears, small concave saddle-shaped or
flattened noses, relatively large ridged tongues that roll over
a protruding lower lip, loose joints, and low muscle tone that
contributes to poor motor skills. People with Down
syndrome frequently have other medical problems. There is
a mild to severe form of mental retardation accompanied by
distinctive physical traits.
• The incidence of Down syndrome increases with increasing
maternal age. The condition can be diagnosed prenatally
with the use of amniocentesis.
• Other Autosomal anomalies include:
• 1 Trisomy 16
• 2 Trisomy 18 (Edwards syndrome)
• 3 Trisomy 13 (Patau syndrome)
• 4 Deletion 22q11.2 (DiGeorge syndrome)
• 5 Cri- Du-Chat Syndrome

There are also structural disorders of the autosomes. The most important are
deletions. Very well known are deletion of short arm of 5 chromosome (Cri du chat
syndrome) and deletion of long arm of 22 chromosome (DiGeorge syndrome).
• DiGeorge syndrome is caused by the interstitial deletion on the long arm of the 22
chromosome. The symptoms are palatal abnormalities, congenital heart disease,
facial dysmorphia, microcephaly, hypocalcemia and thymic hypoplasia with T-cell
immunity defect.

• Edwards syndrome is connected with a trisomy of chromosome 18. The most of

the affected individuals die during the prenatal stage. Newborns have multiple
defects – micrognathia, short neck, congenital heart defects and renal
malformations. The children look weak and fragile.
• The incidence is 1 in 8000. Boys are more affected than girls.
• Bartholin-Patau syndrome, also called
autosomal Trisomy 13, is a very severe condition
first described by Dr. Klaus Patau in 1960. This
genetic disorder is associated with severe
intellectual disability and physical abnormalities
in many parts of the body. The affected
individuals often have heart defects, brain or
spinal cord abnormalities, microphthalmia (very
small or poorly developed eyes), cleft lip, extra
fingers and/or toes, among other features.
• Incidence is 1 out of 10,000 newborns
• Cri-du-chat Syndrome is caused by a deletion (the length
of which may vary) on the short arm of chromosome 5.
Multiple genes are missing as a result of this deletion, and
each may contribute to the symptoms of the disorder. One
of the deleted genes is TERT (telomerase reverse
transcriptase). This gene is important during cell division
because it helps to keep the tips of chromosomes (
telomeres) in tact.
• Babies with cri-du-chat are usually small at birth, and they
may have respiratory problems. Often, the larynx doesn't
develop correctly, which causes the signature cat-like cry.
People who have cri-du-chat have very distinctive features.
They may have a small head (microcephaly), an unusually
round face, a small chin, widely set eyes, folds of skin over
their eyes, and a small bridge of the nose. Several
problems occur inside the body.
•
• Williams syndrome:
• Williams syndrome is a rare genetic disorder that
affects a child's growth, physical appearance, and
cognitive development. People who have Williams
syndrome have missing genetic material from
chromosome 7, including the gene elastin. This
gene's protein product gives blood vessels the
stretchiness and strength required to withstand a
lifetime of use. The elastin protein is made only
during embryonic development and childhood, when
blood vessels are formed. Because they lack the
elastin protein, people with Williams Syndrome have
disorders of the circulatory system and heart.
 Sex chromosome anomalies
• Turner syndrome :occurs when females inherit only one X
chromosome--their genotype is X0 (i.e., monosomy X). If they survive to
birth, these girls have abnormal growth patterns. They are short in
stature, averaging 4 foot 7 inches as adults, and often have distinctive
webbed necks (i.e., extra folds of skin), small jaws, and high arched
palates. They generally lack prominent female secondary sexual
characteristics. They have exceptionally small, widely spaced breasts,
broad shield-shaped chests, Frequency -from 1 in 2,000 to 1 in 5,000
female infants.
• Triple-X syndrome occurs in women who inherit three X
chromosomes--their genotype is XXX. As adults, these "super-females"
or "metafemales" : as they are sometimes known, generally are an inch
or so taller than average with unusually long legs and slender torsos but
otherwise appear normal, have learning difficulties (especially the XXXX
and XXXXX individuals). They frequently are very tall in childhood and
tend to be emotionally immature for their size. Individuals who are
genetic mosaics (XX/XXX) have less noticeable symptoms. Frequency is 1
in 1,000 female infants and it occurs more commonly when the mother
is older.
• Klinefelter syndrome :males inherit one or more extra X chromosomes--their
genotype is XXY or more rarely XXXY or XY/XXY mosaic. In severe cases, they
have relatively high-pitched voices, asexual to feminine body contours as well as
breast enlargement, and comparatively little facial and body hair. They are
sterile or nearly so, and their testes and prostate gland are small. As a result,
they produce relatively small amounts of testosterone. . Like triple-X females
(described above), many Klinefelter syndrome men are an inch or so above
average height. They also are likely to be overweight. They usually have
learning difficulties as children, especially with language and short-term
memory. They are usually capable of normal sexual function, including erection
and ejaculation, unable to produce sufficient amounts of sperm for conception.
Frequency is 1 in 500 and 1 in 1000 male births.
• XYY syndrome :males inherit an extra Y chromosome--their genotype is XYY. As
adults, these "super-males" are usually tall (above 6 feet) and generally appear
and act normal. However, they produce high levels of testosterone. During
adolescence, they often are slender, have severe facial acne, and are poorly
coordinated. They are usually fertile and lead ordinary lives as adults.
Frequency is 1 in 900 male births to as rare as 1 in 1500 or even 1 in 2,000. Also
referred to as Jacobs syndrome.
• What is a chromosome analysis?
• Chromosome analysis is a study of the number and general
structure of all 46 chromosomes; it is also known as a karyotype.
In a standard karyotype, chromosomes from cells in the body
(usually white blood cells) are counted to ensure that the cells
evaluated have the correct number of
• chromosomes, and their structure is evaluated to ensure that
there are no large pieces of material that are missing (deleted),
extra (duplicated), or rearranged in any way. It is important to
realize that standard chromosome analysis may not be able to
detect tiny deletions or duplications of genetic material (other
tests are available that are better able to do this), and will NOT be
able to detect single gene conditions, such as sickle cell disease.
• Hundreds of different types of chromosome abnormalities
causing well described syndromes have been reported in
humans. They fall into 2 categories: numerical and structural
• A numericalchromosome abnormality simply means that a
person has a total number of chromosomes different from 46;
usually 47 or sometimes 45 chromosomes, in each cell of their
body, respectively. Health problems and birth defects are
usually present as a result of having the extra or missing
genetic material. An example of a numerical chromosome
abnormality is Down syndrome, which is typically caused by
having an entire extra chromosome 21, for a total of three
copies of chromosome 21 instead of two.
• The other type of chromosome abnormality, structural, means
that a portion of the genetic material has been rearranged in
some way; for example, a piece of one chromosome may be
attached to another chromosome (translocation), or a piece of
a chromosome may be turned upside down (inversion). A
rearrangement may or may not result in obvious health
problems
• This depends on whether the structural problem ultimately results in a
net gain or loss of chromosome material. If the chromosome material is
simply in a rearranged fashion, yet all of the genetic information is
present, the person may have no clinical symptoms; this is known as a
“balanced” rearrangement. However, this type of chromosome
rearrangement can cause the individual to have an increased chance for
pregnancy losses or infants born with birth defects. This is because
chromosome rearrangements can make it difficult for the genetic
information to be divided equally between each egg/sperm cell. If this
occurs, and then that egg or sperm cell is used in reproduction, there can
be too much or too little genetic material in the resulting fetus. The
pregnancy is "unbalanced" chromosomally, and may miscarry or result in
the birth of a child with health and/or learning problems.
• About 1 in 500 persons in the general population carry a rearrangement in
their chromosome material. Persons with family or personal histories of
multiple pregnancy losses, unexplained stillbirths, or early infant deaths,
may be at a slightly greater chance to have a rearrangement in their
chromosomes
• Even when both parents have normal chromosomes
and the baby has a normal chromosome study on
an amniocentesis, there is still a 2-3% chance for
the baby to have a birth defect. Chromosome
analysis only provides information relating to the
number and structure of chromosomes, and does
not evaluate for single gene disorders. It is
important to understand the difference between a
chromosome study and a separate DNA or
biochemical test for the function of a specific gene.
• Unfortunately at present, there is no genetic test
that screens for everything.