Genetic

Chapter 8 Disorder

8.1 Chromosomal 8.1 Chromosomal Abnormalities and

Abnormalities and
Syndromes
Syndromes
In certain situations e.g., due to environmental radiation,
8.2 Monogenic Disorders
food intake or internal genetic conditions, chromosomes
and Pedigree
may suffer damage or may change in numbers. The
Mapping
change in structure is called structural chromosomal
8.3 Polygenic Disorders abnormality (or aberration) and the change in number is
called numerical chromosomal abnormalities. When one
chromosome of the pair is absent, the condition is called
monosomy (2n-1) for that chromosome e.g., monosomy of
chromosome 1. When a chromosome is present in three
copies, this condition is called trisomy (2n+1) e.g., trisomy
of chromosome X. It is important to notice that both
monosomy and trisomy come under the broad category of
aneuploidy. However, when the entire set of chromosome
is multiplied (e.g., 69: 23 ´ 3, 92: 23 ´ 4), the condition
is called polyploidy. The artificial breeding of plants has
resulted in several polyploid varieties that we commonly
use in our food. For example, bread wheat has six sets
of chromosomes (hexaploid), cabbages or mustards are

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tetraploids. Likewise, banana and apple are triploid (3 sets

of chromosomes), strawberry and sugar cane are octoploid
(8 sets of chromosomes). Both structural or numerical
changes can result in significant changes in phenotypic
condition in the form of diseases or syndromes.
8.1.1 Structural chromosomal abnormalities
Structural chromosomal abnormalities may be of following
types:
1. Deletion— In deletion, a segment of a chromosome
breaks away leading to shortening of the chromosome
[Fig. 8.1(a)]. For example, retinoblastoma is caused due
to deletion of a portion of chromosome 13. Sometimes
when two ends of a chromosome are deleted, they can
reattach to form a ring chromosome.
2. Duplication— Duplication refers to when a segment
of the chromosome gets repeated resulting in a longer
chromosome [(Fig. 8.1(b)]. This can lead to conditions
e.g., Charcot-Marie-Tooth disease caused due to
duplication of genes on chromosome 17.
3. Inversion— In inversion, a segment of the chromosome
breaks away, completely reverses itself and reattaches
with the chromosome. Here the overall length of the
chromosome remains same but the orientation of genes
is reversed by 180 degrees [(Fig. 8.1(c)]. For example,
RCAD syndrome caused by inversion of a segment of
chromosome 17.
4. Translocation— In translocation, a segment of a
chromosome breaks away and reattaches itself with
another chromosome. If there is a mutual exchange
of segments between two chromosomes, it is called

A A A A A A A
B A B B B E B L B
L
C C C C C D C C
M M
N N
D D D D D C D D
E E E D E B E O E O
F F F E F F F P F
F Q P
Q
(a) (b) (c) (d)

Fig. 8.1: (a) Deletion (b) Duplication (c) Inversion and (d) Translocation

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reciprocal translocation. Example: Burkitt’s lymphoma,

where exchange of materials happens between
chromosomes 8 and 14. If a segment of a chromosome
breaks away and attaches with another chromosome,
without mutual exchange, it is called Robertsonian
translocation. This may result in decrease of chromosome
number of the cell [Fig. 8.1(d)].
8.1.2 Numerical chromosomal abnormalities
Some commonly observed syndromes/diseases due to
numerical chromosomal abberations are described in
following section. The term syndrome is generally referred
to a group of symptoms which consistently occur together,
or a condition characterised by a set of associated
symptoms. A disease refers to abnormal physiological
response to internal or external factors e.g., fever caused
due to microbes.
1. Down's Syndrome
Incidence: Occurs in approx.1 per 800 live births.
Chromosomal basis: Down syndrome is a genetic condition
that arises due to presence of an extra chromosome 21.
Here, chromosome 21 is repeated thrice (trisomy 21),
instead of showing up twice in a normal individual. The
karyotype of Down syndrome is represented as 47, XX,
+21 (females) and 47, XY, +21 (males) [(Fig. 8.2(a)].

(a) (b)

Fig. 8.2: Karyogram of (a) an individual affected with down syndrome (b) an individual affected
with Klinefelter's
The trisomic condition is usually caused by an error in the
process of cell division called non disjunction, i.e., inability
of chromosomes to separate at the time of cell division.

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The possibility of having a Down's syndrome baby in

the family increases with the maternal age. It has been
reported that more than 85% Down syndrome babies
are born in mothers over 35 years of age, at the time of
pregnancy.
Clinical symptoms: Some of the distinguishing features of
Down's syndrome are: flat face, slanting eye, small mouth,
protruding tongue, flattened nose, short neck, short arms
and legs, single deep crease across the palm, low IQ,
stunted growth, muscular hypotonia, under developed
gonads. Down's syndrome babies also show breathing,
heart or hearing problems.
Diagnosis and Treatment: Down
syndromes are usually diagnosed
by an extra chromosome 21 in the
karyotype. There is no single standard
treatment protocol for Down syndrome.
Treatments are tailored on specific
set of conditions presented by these
individuals. At early age, children with
Down's syndrome can benefit from
speech therapy, physiotherapy and
taking nutritional supplements.
In early 1900s, on an average,
Osteoporosis
Down's syndromes used to live until
age 9. Now with the advances in
Feminine abdomen
abdom
diagnostic and treatment technologies,
Small penis the age expectancy has increased up to
60 and even longer.
2. Klinefelter's syndrome
Incidence: Occurs in approximately 1
out of 1000 new born males.
Chromosomal basis: Genotype:
47, XXY. Affects males. The extra
chromosome is not transmitted
genetically (i.e., a Klinefelter newborn
cannot have a Klinefelter father) but
arises from inability of X chromosome
to detach itself from the pair during
meiosis (at the time of gamete
formation). Fertilisation of an XX ova
Fig. 8.3: Individual with with a Y sperm produces an XXY
Klinefelter's Syndrome
zygote.

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Clinical Symptoms: Klinefelter's syndrome children are

unusually tall for their age, have reduced facial and body
hair, smaller testes, enlarged breasts and coarse voice
[Figs. 8.2(b) and 8.3].
Diagnosis and Treatment: One of the most frequent
methods to diagnose Klinefelter syndrome is through Barr
body test of buccal smear. Normally no Barr body appears
in the male buccal smear. However, in Klinefelter one
Barr body shows up, indicating the presence of an extra X
chromosome.
At the time of birth, babies with Klinefelter differ a little
from other normal babies. However, as the age increase
the differences become noticeable, especially at the time
of puberty.
People with Klinefelter's syndromes are often treated
with testosterone to look masculine. They also need to be
psychologically counselled to control depression leading to
aggression.
3. Turner's Syndrome
Incidence: Occurs in 1 in 2,500 newborn girls, frequently
observed in miscarriages and still births.
Chromosomal basis: Affects females, arises due to the
missing X chromosome in affected females. This is called
monosomy X and the karyotype is represented as: 45, X.
A cell division error during meiosis of an ovum results in
an ovum with no X chromosome and other
with two X chromosomes. The ovum with no
X chromosome fuses with sperm with one
X chromosome to generate 45, X condition.
Mothers with Turner syndrome cannot
pass the condition to their daughters i.e.,
this condition is not inherited.
Clinical symptoms: Turner syndromes
are diagnosed by following features — short
stature, webbed neck (i.e., the neck skin is
unusually loose and can be pulled several Fig. 8.4: Turner's Syndrome
centimetres of the neck), small breasts, low
set ears (i.e., ears are placed below the normal position),
swollen hands and feet. Furthermore, ovaries are under
developed and menstrual periods are usually absent
(Fig. 8.4).

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Diagnosis and treatment: Prenatal chromosomal

diagnosis usually happens through amniocentesis or
chorionic villus sampling. At puberty the first test is that
of Barr body of buccal smear. The absence of Barr body is
the first indicator to follow up the condition with a detailed
investigation. As with other syndromes, there is no
permanent cure. However, growth and ovarian functions
can be strengthened by the controlled administration of
hormones androgen and estrogen.

Box 1

Famous people with syndromes

1. Isabelle Springmühl is a famous fashion designer with Down syndrome. Achieving
this feat wasn’t easy as several universities rejected her application to study fashion
design. But she persisted and has showcased her talent in London, Rome and Mexico.
2 It’s commonly believed that the famous US president, six feet two inches tall, Mr.
George Washington had Klinefelter Syndrome. He had no children and adopted two
later in his life.
3. Lauren Foster, a South African model was born male and diagnosed with XXY
Klinefelter condition. However, Lauren chose to identify herself with feminine features
and transitioned to a full female phenotype in her teens. Lauren became a successful
model and appeared in Vogue Magazine. She even wanted to contest for the Miss
South Africa pageant but was disqualified.
4. Hollywood TV, Film and Stage actress Linda Hunt was diagnosed with Turner
syndrome. Linda started her career as a singer and made her Hollywood debut with
Popeye film version. Linda has won 13 awards that include the 2012 Teen Choice
Award and the 1984 Oscar Award for the Best Supporting Actress.
5. Dr. Catherine Ward Melver is a famous medical genetics doctor in the US. The 4 feet
and 8 inch tall, Dr.Melver was diagnosed with Turner syndrome when she was seven
years of age. Dr.Melver adopted a 4-year-old Turner syndrome girl, Zoe, from China.

8.2 Monogenic Disorders and Pedigree Mapping

(Cystic Fibrosis, Sickle Cell Anemia,
Haemophilia, Color Blindness)
Monogenic disease is caused by an error in a single gene.
According to current estimate over 10,000 of human
diseases are estimatd to be monogenic affecting millions
of individual world wide. The nature of disease, its sign
and symptoms depend on the functions performed by the

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modified or defective gene. These diseases are inherited

according to Mendel’s Laws. In some cases, the mutation
can be spontaneous and where we will not get the previous
family history. There may be single mutation in one gene
causing specific disease like sickle cell anemia or multiple
types of mutation in one gene and producing the same
disease like cystic fibrosis (more than 200 different types
mutation can occur in one gene).
The single-gene or monogenic diseases can be classified
into the following categories according to the inheritance
pattern as follows:
• Autosomal recessive Male
• Autosomal dominant Female
• X-linked recessive
Affected individual
• X-linked dominant
For diagnosis of the inherited genetic disease mating
one has to understand the concept of pedigree Offspring in birth order;
analysis. The pedigree analysis is the process I and II are generations;
offspring numbered II-1 and II-2
of interpretation of information displayed as a
family tree. If more than one person in a family Identical twins
is involved with a disease then the pedigree Non-identical twins
analysis can be done. Specific symbols are
used to indicate different aspects of a pedigree Fig. 8.5: Symbols used in
as shown in (Fig. 8.5). pedigree

Autosomal recessive disorder

The word ‘Recessive’ indicates that 2 copies of the genes
are needed to have the trait and disorder in case of mutated
gene. Out of the 2 copies one gene is inherited from father
and one from mother. If an individual carries one defective
recessive and one normal recessive gene then he or she
will be the carrier and not develop the disease. On the
basis of statistical projection it is estimated that every
human being carries about 5 or more defective recessive
genes which can cause a genetic disease. The disease
phenotype of a recessive disorder is due to homozygosity
of a recessive allele and the unaffected phenotype is
secondary to corresponding dominant allele. This can be
explained with the example of sickle cell anemia which is
a autosomal recessive disease. Sickle cell disease is caused
by a mutation in the hemoglobin-β gene found on
chromosome 11. This results in a defective haemoglobin

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(Hb). After giving up oxygen these defective Hb molecules

cluster together resulting in formation of rod like
structures. The red blood cells become stiff and assume
sickle shape (Fig. 8.6).

Fig. 8.6: Peripheral blood shows sickling of red blood

cells in case of sickle cell disease

Sickle cell anemia is determined by an allele which we

can designate as s and the normal condition by S. The
person affected by the disease will have a genotype of
s/s and unaffected ones will be either S/S or S/s. We
can make a projected pedigree of the disease as follows
assuming that both parents are carriers (S/s) (Fig. 8.7):

s Carrier
s s
s s

s s s s

Fig. 8.7: A cross showing inheritance of sickle cell anemia disease

Sickle cell anemia is particularly common among people

whose ancestors originated from sub-Saharan Africa,
South America, Cuba, Central America, Saudi Arabia,
India, and Mediterranean countries. In India it is common

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among people of the Deccan plateau of central India with a

smaller focus in the north of Kerala and Tamil Nadu.
Other examples of autosomal recessive diseases include
cystic fibrosis, Tay Sach’s disease and phenylketonuria.
Individual with cystic fibrosis produce mucus that is
abnormally thick and sticky that can damage different
organs specially lungs resulting in chronic infections.
Tay-Sachs disease is due to absence of an enzyme called
hexosaminidase A which results in a fatty substance
accumulation in nerve cells particularly affecting the
brain. It is a fatal disease manifest in childhood. One in 27
persons of European Ashkenazi Jewish origin individuals
carries the Tay-Sachs gene. Phenylketonuria is caused by
a mutation in phenylalanine hydroxylase gene resulting
in increase in phenylalanine in the blood.
Autosomal dominant disorder
In this kind of inheritance the normal allele is recessive
and the abnormal allele is dominant. A rare autosomal
dominant disorder Achondroplasia may be considered
as an example which leads to a type of Dwarfism in the
affected individuals (Fig. 8.8).
In this condition normal people have genotype d/d,
affected individual with mild disease have D/d and severly
affected have D/D which is often lethal. So most of the
surviving cases of achondroplasia are heterozygotes.
Huntington’s disease is another example of a rare
autosomal dominant disorder which affects nervous
system.
Fig. 8.8 Schematic diagram
X-linked recessive disorder of Achondroplasia
In the X-linked recessive inheritance in the mother (XX) causing Dwarfism
the affected gene remains on one X chromosome, as a
result she becomes the carrier and usually only males
(XY) are affected by the disorder (Fig. 8.9). In the progeny
the men pass the Y chromosome on to their sons and
their X chromosomes to their daughters. So a man who is
affected will not pass it on to his sons but all his daughters
will be carriers.
Some examples of X-linked recessive disorders are,
Haemophillia, and Duchenne Muscular Dystrophy.
Haemophilia is a bleeding disorder associated with
mutation in coagulation factor VIII gene (type A) or factor IX

Fig. 8.8 courtesy: https://www.shutterstock.com/image-vector/dwarfism-257159986

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Fig. 8.9: Inheritance of an X-linked disorder

gene (type B). Mutations in coagulation factor genes result

in the production of an abnormal version of coagulation
factor VIII or IX, or reduced amount of one of these
proteins. The altered or missing coagulation factor cannot
effectively complete the blood clotting process leading to
spontaneous bleeding or increased bleeding tendencies.
Duchenne Muscular Dystrophy (DMD) is caused by
mutation of dystrophin gene resulting in reduction/
absence of dystrophin or presence of abnormal protein.
Dystrophin abnormality or deficiency leads to dystrophy or
degeneration of muscle making them more fragile and weak.

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X-linked dominant disorder

In this type of inheritance the affected males pass on the
mutated dominant gene to all their daughters but to none
of their sons (Fig. 8.10a). In case of affected female married
to unaffected male the condition is passed on to half of
their sons and daughters. (Fig. 8.10b). Examples of such
disorders are hypophosphatemia, a type of vitamin D
resistant rickets and Alport syndrome, which is associated
with progressive hearing loss and kidney disease.

X-linked dominant affected Father X-linked dominant affected Mother

Affected Unaffected Unaffected Affected

Father Mother father Mother

XY XX XY XX
Unaffected Unaffected
Affected Affected

XY XX XY XX XY XX XY XX

Unaffected Affected Unaffected Affected Unaffected Affected Affected unaffected

(a) son daughter son daughter (b) son daughter son daughter

Fig. 8.10 Inheritance of an X-linked dominant disorder through (a) affected father
and (b) affected mother

8.3 Polygenic Disorders (Hypertension,

Coronary Heart Disease, and Diabetes)
A polygenic disorder is caused by the defect or combined
action of more than one gene. The classical examples of
polygenic disease include hypertension, coronary heart
disease and diabetes. As the pathogenesis proceeds such
diseases depend on the simultaneous association of
several genes and therefore, they can not be explained as
monogenic diseases.
Diabetes mellitus is an important example of polygenic
disease. It is a heterogeneous group of disorders

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characterised by persistent high blood sugar level or

hyperglycemia. There are two most common forms of
diabetes: Type 1 diabetes (T1D, previously known as insulin
dependent diabetes or IDDM) and type 2 diabetes (T2D,
previously known as non-insulin-dependent diabetes or
NIDDM). Type I diabetes is caused by the destruction
of the beta cells of the pancreas due to immunological
abnormality. This type constitutes approximately 10%
of all cases of diabetes. Life long treatment with insulin
injection is needed for these cases. Type 2 diabetes is the
commonest form of disease and represents about 90% of
cases. It is caused by impaired insulin secretion from beta
cells of pancreas and also peripheral insulin resistance.
Insulin is needed for transporting glucose from blood to
inside the cells like muscle cells for producing energy and
maintaining cell function.
Hypertension or presistent increase in blood pressure
is a major risk factor for renal, heart and stroke involving
brain. This is leading cause of global mortality and
morbidity. The normal blood pressure (BP) as <120
(systolic) /<80 (diastolic) mm Hg; elevated BP 120-129/<80
mm Hg; hypertension stage 1 is 130-139 or 80-89 mm Hg,
and hypertension stage 2 is ≥140 or ≥90 mm Hg.

Fig. 8.11: (a) Normal heart and artery and (b) Artery with plaque build-up in
coronary heart disease

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The Coronary Heart Disease (CHD) develops due to

narrowing of the coronary artery which supplies blood to
heart muscles by gradual build-up of fatty material on
its wall (Fig. 8.11). This accumulation of fatty material
on the wall of the artery is called atherosclerosis. Due
to narrowing of the coronary artery by atherosclerosis it
can not supply oxygen rich blood to heart muscle which
needs it for its continuous activity. This phenomenon of
reduction of blood supply is called ischemia. That is why
previously coronary heart disease was called as ischaemic
heart disease.

Box 2

Mitochondrial inheritance and diseases

As you have studied earlier, mitochondria are organelle present in the cytoplasm of the
cells which are primarily responsible for energy production for all cellular activities.
Mitochondria produce energy by ATP (adenosine triphosphate). The ATP production
depends on a series of well regulated chemical reaction under specific interaction of
different enzymes. There are genes in the mitochondria which contain information or
codes for these critical enzymes. Any defect or mutation in these genes can affect the
ATP production and cellular function. There are variable number of mitochondria in
different cell types. Cells in organs like brain, heart, kidneys, muscle and liver which
are metabolically very active needs continuous high energy supply. These cells have a
large number of mitochondria. In a defect with mitochondrial gene if all mitochondria
are affected then it will not be possible for the person to survive. So, in human disease
due to mitochondrial gene defect the symptoms and disease severity depends on the
ratio of normal and abnormal mitochondria in cells.
Mitochondria are the organelle which contain DNA in circular form, and in animals
it is the only organelle in addition to nucleus which contain DNA and gene. The sperm
contains very low number of mitochondria and mitochondrial gene. So in the offspring
the mitochondrial genes are inherited from the mother. Thus a father with mitochondral
gene defect can not transmit the disease to his offspring. The concept of mitochondrial
inheritance is explained in the Fig. 8.12.

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Grandmother with a faulty

(mutated) mitochondrial gene

Affected Affected Unaffected Unaffected

son daughter son daughter

Key Unaffected Affected Normal Faulty

daughter individual mitochondia mitochondria

Fig. 8.12: Diagram showing Mitochondrial inheritance in a family with a faulty (mutated)
mitochondrial gene

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Summary
• Haploid cells have only one copy of the chromosome while
diploid cells have two copies of the same chromosome.
• Any deviation where one or few chromosomes are either
absent or present in multiple copies is called aneuploidy.
• In polyploidy condition, the entire set of chromosome is
multiplied.
• A syndrome is a specific collection of signs or symptoms
suggesting a particular disease, while a disease is a
broader term that refers to abnormal physiological
response to internal or external factors.
• Symptoms are subjective and signs are objective.
• Structural chromosomal abnormalities can be caused
by deletion, duplication, inversion and translocation.
• Monogenic disease is caused by modifications in a
single gene. They can be classified into the following:
autosomal recessive, autosomal dominant, X-linked
recessive and X-linked dominant.
• Polygenic disorder is caused by the defect or combined
action of more than one gene.
• Mitochondrial inheritance and diseases are caused due
to defect or mutation in the genes coding for critical
enzymes present in the mitochondria.
• Four types of structural chromosomal abnormalities
exist: deletion, duplication, inversion and translocation.
• Down syndrome occurs due to trisomy 21 and are
characterised by features like moon like face, protruding
tongue, muscular hypotonia, palmar crease and so on.
• Klinefelter syndrome occurs due to presence of an extra
X chromosome in males and is characterised by tall
height, enlarged breasts, coarse voice, hypogonadism
and so on.
• Turner syndrome occurs due to absence of one X
chromosome in females and is characterised by short
stature, webbed neck, small breasts, no menstruation
and so on.

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Exercises
1. Define following terms: dominant, recessive, homozygous,
heterozygous, phenotype and genotype.
2. Describe the origin, symptoms and treatment of Down
syndrome.
3. Describe the origin, symptoms and treatment of Klinefelter
syndrome.
4. Describe the origin, symptoms and treatment of Turner
syndromes.
5. Describe various structural chromosomal abnormalities.

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