GENETIC

DISORDERS
LEARNING OBJECTIVES:
At the end of this Unit, 2nd year students will be able to:
• 1. Differentiate between Genetic & Congenital disorder
• 2. Define the following terminologies related to genetic
disorders:
• i. Trisomy
• ii. Monosomy
• iii. Polysomy

• 3. Discuss the Chromosomal defects with special emphasis

on aneuploidy
• 4. Describe the pathophysiology and the clinical
manifestation of the following genetics
• disorders.
• Down’s syndrome
• Turner’s syndrome
• Klinefelter’s syndrome
GENETICS

Genetics is a branch of biology concerned with the study of genes,

genetic variation, and heredity in organisms.

Genes

They are basic units of inheritance and they ultimately

influence all aspects of body structure and function.

DNA

It is a long molecule that is made up of thousand s segments

of genes.
Chromosomes
chromosomes are large structures made up of DNA.
Brief reminder
Autosomes
Chromosomes 1-22
An individual inherits one chromosome from each parent
An individual therefore inherits a paternal copy and a
maternal copy of an Autosomal gene

Sex chromosomes
X and Y
A female inherits an X from their mother and an X from
their father
A male inherits an X from their mother and the Y from
their father
Genotype:
The genetic make up of an individual
is called genotype.
Phenotype:
The genetic make up expressed in a
body is called Phenotypes. It is the
physical or out ward expression of the
gene.
An individual’s genotype is the combination of alleles that they possess for a specific
gene. An individual’s phenotype is the combination of their observable characteristics or
traits. While an organism’s genotype is directly inherited from its parents, phenotype is
merely influenced by genotype. Environmental factors can also affect phenotype. )
Environmental factors that may influence the phenotype include nutrition, temperature,
humidity and stress
Alleles:

Alternative form of a gene that code for the same trait and

are at the same location on homologous chromosomes are

called alleles.
Dominant

An allele that dominates or masks the presence of another

allele and are fully expressed is said to be dominant and the

trait expressed is a dominant trait.

Recessive

The alleles whose presence is completely masked is said to be

recessive and the trait is control is a recessive trait

GENETIC DISORDERS

Genetic disorders are the result of genes or chromosomal

alterations.

Mutation

A mutation is a permanent change in genetic material.

Some mutations results in serious disorders.

• Single Gene disorders

• Mutifectorial disorders

• Chromosomal disorders
Structure of chromosome based on position of centromere

Each chromosome has two arms, labeled p (the shorter of the two) and q

(the longer).

The p arm is named for "petite" meaning 'small'; the q arm is named q

simply because it follows p in the alphabet.

They can be connected in either metacentric, submetacentric, acrocentric or

telocentric manner.
KEY POINTS:
• Genetic disorders are inherited as autosomal
dominant disorders, in which each child has a
50% chance of inheriting the disorder, or as
autosomal recessive disorders, in which each child
has a 25% chance of

• being affected , a 50% chance of being a carrier,

and a 25% chance of being unaffected.

• Chromosomal disorders reflect events that

occur at the time of meiosis and result from
defective movement of an entire chromosome or
from breakage of a chromosome with a loss or
translocation of genetic material.
Chromosomal Disorders:
• Chromosomal disorders form a major category of genetic
disease, accounting for a large proportion of reproductive
wastage (early gestational abortions), congenital
malformations, and intellectual disability.
• During meiosis, the double sets of 22 autosomes and the 2
sex chromosomes (normal diploid number) are reduced to
single sets haploid number in each gamete. At the time of
conception , the haploid number in the ovum and that in
the sperm join and restore the diploid number of
chromosomes.
• Chromosomal abnormalities are commonly described
according to the shorthand description of the karyotype. In
this system, the total no. of chromosome is given first,
followed by sex chromosome complement, and then the
description of any abnormality.
• For example, a male with trisomy 21 is designated 47,XY,
+21.
Chromosomal Disorders:
• In these disorders, entire chromosomes, or large
segments of them, are missing, duplicated, or
otherwise altered.
Can be organized into two basic groups:
1) Numerical Abnormalities: When an individual is
missing either a chromosome from a pair (monosomy)
or has more than two chromosomes of a pair (trisomy)
2) Structural Abnormalities: When the chromosome’s
structure is altered.
Structural Chromosomal
Abnormalities:
• Structural changes in chromosomes usually result from
breakage in one or more of the chromosomes followed by
rearrangement or deletion of chromosome parts.
• Among the factors believed to cause chromosome
breakage are exposure to radiation sources, such as x-
rays; influence of certain chemicals; extreme changes in
the cellular environment ; and viral infections.
• Deletion: There can be a deletion of the broken portion of
the chromosome. Deletions can be large or small, and can
occur anywhere along a chromosome. When one
chromosome is involved, the broken parts may be
inverted.
• Duplications: occur when part of a chromosome is
abnormally copied (duplicated). This type of chromosomal
change results in extra copies of genetic material from the
duplicated segment.
• Inversion: occurs when a chromosome breaks in two
places; the resulting piece of DNA is reversed and re-
• Isochromosome formation when the
centromere, or central portion separates
horizontally instead of vertically.
• Ring formation: when deletion is followed by
uniting the chromatids to form a ring.
• Translocation occurs when there are
simultaneous breaks in two chromosomes from
different pairs, with the exchange of chromosome
parts.
• Robertsonian translocation also called centeric
fusion involves two acrocentric chromosomes in
the centromere is near the end, most commonly
chromosomes 13 and 14 or 14 and 21.
• The manifestations of aberration depends in
chromosome structure depend to a great extent
on the amount of genetic material that is lost or
displaced.
Numeric Disorders Involving
Autosomes:
• Having an abnormal number of chromosomes is
referred to as aneuploidy.
• Among the causes of aneuploidy is a failure of the
chromosomes to separate during oogenesis or
spermatogenesis.
• This can occur in either the autosomes or the sex
chromosomes and is called nondisjunction.
• Nondisjunction gives rise to germ cells that have
an even number of chromosomes (22 or 24).
• The products of misconception from this even
number of chromosomes, 45 or 47.
Monosomy
Monosomy is a form of aneuploidy with the presence of only one
chromosome (instead of the typical two in humans) from a pair.
Monosomy of the sex chromosomes (45,X)
Disomy
Disomy is the presence of two copies of a chromosome. For
organisms such as humans that have two copies of each
chromosome (those that are diploid), it is the normal condition.
Trisomy
Trisomy refers to the presence of three copies, instead of the
normal two, of a particular chromosome.
The presence of an extra chromosome 21, which is found in Down
syndrome, is called trisomy 21.
• Monosomy refers to the presence of only one
member of a chromosome pair. The defects
associated with monosomy of the autosomes are
severe and usually cause abortion.
• Monosomy of the X chromosomes (45, X), or
Turner syndrome, causes less severe defects.
• Polysomy, or the presence of more than two
chromosomes set, occurs when a germ cell
containing more than 23 chromosomes is involved
in conception.
• Trisomy 18 (Edwards syndrome) and trisomy 13
(Patau syndrome) share several karyotypic and
clinical features with trisomy 21 (Down
syndrome).
Polysomy:
Polysomy refer to the presence of more then two copies
of chromosome.
Example Trisomy, tetrasomy and pentasomy
Tetrasomy and pentasomy are the presence of four or
five copies of a chromosome, respectively.
Although rarely seen with autosomes, sex chromosome
tetrasomy and pentasomy have been reported in
humans, including XXXX, XXXY, XXYY, XYYY,
XXXXX, XXXXY, XXXYY, XXYYY and XYYYY
Down Syndrome
• First described in 1866 by John Langdon Down,
trisomy 21 or Down Syndrome.
• It is the most common chromosomal disorder.
• Approximately 95% of cases of Down Syndrome are
caused by nondisjunction or an error in cell division
during meiosis, resulting in a trisomy of chromosome
21.
• A rare form of Down syndrome can occur in the
offspring of people there has been a robertsonian
translocation involving the long arm of chromosome
21q and long arm of one the acrocentric chromosomes
(most often 14 or 22). The translocation adds to the
normal long arm of chromosome 21.Therefore, the
person with this type of Down syndrome has 46
chromosomes, but essentially a trisomy of 21q.
 Down Syndrome
• Down syndrome occurs because of an abnormality
characterized by an extra copy of genetic material on all or
part of the 21st chromosome.
• Every cell in the body contains genes that are grouped along
chromosomes in the cell's nucleus or center. There are
normally 46 chromosomes in each cell, 23 inherited from your
mother and 23 from your father. When some or all of a
person's cells have an extra full or partial copy of
chromosome 21, the result is Down syndrome.
• The most common form of Down syndrome is known as
Trisomy 21, a condition where individuals have 47
chromosomes in each cell instead of 46. This is caused by an
error in cell division called nondisjunction, which leaves a
sperm or egg cell with an extra copy of chromosome 21
before or at conception.
• Trisomy 21 accounts for 95% of Down syndrome cases, with
88% originating from nondisjunction of the mother's egg cell.
• The remaining 5% of Down syndrome cases are due to
conditions called mosaicism and translocation.
• Mosaic Down syndrome results when some
cells in the body are normal while others have
Trisomy 21.
• Robertsonian translocation occurs when
part of chromosome 21 breaks off during cell
division and attaches to another chromosome
(usually chromosome 14). The presence of
this extra part of chromosome 21 causes
Down some syndrome characteristics.
Although a person with a translocation may
appear physically normal, he or she has a
greater risk of producing a child with an extra
21st chromosome
Risk factor
• The risk of having a child with Down syndrome increases with
maternal age. The reason for the correlation between
maternal age and nondisjunction is unknown.
• The risk of having a baby with Down syndrome is
about
1. 1 in 1,300 at age 25
2. 1 in 1,000 at age 30
3. 1 in 400 at age 35
4. 1 in 100 at age 40
5. 1 in 35 at age 45
Physical Signs of Down Syndrome
• A child with Down Syndrome has specific physical characteristics
that are classically evident at birth. These features include:
• Flat face with an upward slant to the eye,
• short neck, and abnormally shaped ears
• Deep crease in the palm of the hand
• White spots on the iris of the eye
• Poor muscle tone, loose ligaments
• Small hands and feet
• Congenital heart disease
• Hearing problems
• Intestinal problems, such as blocked small bowel or esophagus
• Celiac disease
• Eye problems, such as cataracts
• Thyroid dysfunctions
• Skeletal problems
• Dementia—similar to Alzheimer’s
Treatment for Down Syndrome
• Because there is no cure, the goals of Down
syndrome treatment are to control symptoms and
manage any resulting medical conditions. This
includes regular checkups and screenings,
medications, and surgery. Counseling and support
groups are also aspects of treatment for those
who need help in coping with the emotional and
practical aspects of Down syndrome.
Numeric Disorders Involving
Sex Chromosomes:
• Chromosomal disorders associated with the sex
chromosomes are much more common than
those related to the autosomes, except for
trisomy 21. Furthermore, imbalances (excess or
deletions) are much better tolerated than those
involving the autosomes.
• This is related in a large part to two factors that
are
peculiar to the sex chromosomes:
• 1. The inactivation of all but one X
chromosome
• 2. The modest amount of genetic material that
is carried on the Y chromosome
• Although girls normally receive both a paternal and a
maternal X chromosome, the clinical manifestations of X
chromosome abnormalities can be quite variable
because of the process of X inactivation.
• In somatic cells of females, only one X chromosome is
transcriptionally active. The other chromosome is
inactive. The process of X inactivation, which is random,
occurs early in embryonic life and is usually complete at
about the end of the first week of development. After
one X chromosome has become inactivated in a cell, all
cells descended from that cell have the same inactivated
X chromosome.
• Although much of one X chromosome is inactivated in
females, several regions contain genes that escape
inactivation and continue to be expressed by both X
chromosomes.
• These genes may explain some of the variations in
clinical symptoms seen in cases of numeric
abnormalities of the X chromosome, such as Turner
syndrome.
• It is well known that the Y chromosome
determines the male sex.
• The gene that dictates testicular development
(Sry: sex-determining region Y gene) has
been located on its distal short arm. Recent
studies of the Y chromosome have yielded
additional information about gene families in
the so-called “male-specific Y” or MSY region.
• All of these are believed to be involved in
spermatogenesis. A few additional genes with
homologs on the X chromosome have been
mapped to the Y chromosome, but to date, no
disorders resulting from mutations in these
genes have been described.
Turner’s Syndrome:
• Primary hypogonadism in phenotypic females.
• Results from partial or complete monosomy of an
X chromosome.
• Most common cause (60% cases) is absence of
one X chromosome (45, X/0).
• Some women with Turner syndrome may have
part of the X chromosome, and some may display
a mosaicism with one or more additional cells
lines (20% cases).
• This disorder affects approximately 1 of
every 2500 live births and is the most
frequent occurring genetic disorder
in women.
Sign & Symptoms:
• Characteristically, the girl with Turner syndrome is short
in stature, but her body proportions are normal.
• Females with Tuner syndrome lose the majority of their
oocytes by the age of 2 years. Therefore, they do not
menstruate and shows no signs of secondary sex
characteristics.
• There are variations in the syndrome, with abnormalities
ranging from essentially none to cardiac abnormalities
such as bicuspid aortic valve and coarctation of the aorta,
problems with hearing and vision, posteriorly rotated ears,
a small size mandible, a horseshoe kidney, and a small
webbed neck.
• Women with Turner syndrome have been found to develop
autoimmune disorders associated with male
predominance, such as type 1 diabetes mellitus and
Hashimoto thyroiditis.
• Although most women with Turner syndrome have normal
intelligence, they may have problems with visuospatial
Diagnosis:
• The diagnosis of Turner syndrome often is delayed
until late childhood or early adolescence in girls who
do not present with the classic features of the
syndrome.
• Only about 20% to 33% of affected girls receive a
diagnosis as a newborn because of puffy hands and
feet or redundant nuchal skin.
• Another 33% are diagnosed in mid-childhood
because of short stature.
• The remainder of the girls are mainly diagnosed in
adolescence when they fail to enter puberty.
• It is important to diagnose girls with Turner syndrome
as early as possible so treatment plans could be
implemented and managed throughout their lives.
Management:
• The management of Turner syndrome begins
during childhood and requires ongoing
assessment and treatment.
• Growth hormone therapy generally can result
in a gain of 6 to 10 cm in final height.
• Estrogen therapy, which is instituted around
the normal age of puberty, is used to promote
development and maintenance of secondary
sexual characteristics.
Klinefelter’s Syndrome
• Klinefelter syndrome is a condition of testicular dysgenesis
accompanied by the presence of one or more extra X
chromosomes in excess of the normal male XY complement.
• Most males with Klinefelter syndrome have one extra X
chromosome (47,XXY).
• In rare cases, there may be more than one extra X
chromosome (48,XXXY).
• The presence of the extra X chromosome in the 47,XXY male
results from nondisjunction during meiotic division in one of the
parents.
• The extra X chromosome is usually of maternal origin, but
approximately 1/3 of the time, it is of paternal origin.
• The cause of the nondisjunction is unknown. Advanced
maternal age increases the risk, but only slightly.
• Klinefelter syndrome occurs in approximately 1 per 1000
newborn male infants. It has an incidence of 1.7 in 1000 male
infants.
Sign & Symptoms:
• The disorder usually is diagnosed at puberty or during an
infertility evaluation.
• Klinefelter syndrome is characterized by enlarged
breasts, sparse facial and body hair, small testes, and the
inability to produce sperm.
• Regardless of the number of X chromosomes present, the
male phenotype is retained.
• The condition often goes undetected at birth. The infant
usually has normal male genitalia, with a small penis and
small, firm testicles.
• At puberty, the intrinsically abnormal testes do not
respond to stimulation from the gonadotropins and
undergo degeneration. This leads to a tall stature with
abnormal body proportions in which the lower part of the
body is longer than the upper part.
• In adolescents, the body build may become heavy, with a
female distribution of subcutaneous fat and variable
degrees of breast enlargement (gynecomastia 40%),
small testicles (2.5 cm long), tall stature, and an arm
• Klinefelter syndrome is the most common cause of
hypogonadism in males; testosterone levels are about
half the normal value. The follicle-stimulating hormone
and lactate dehydrogenase levels are increased.
• There may be deficient secondary male sex
characteristics, such as a voice that remains feminine
in pitch and sparse beard and pubic hair.
• Although the intellect usually is normal, most 47,XXY
males have some degree of language impairment may
be useful for future family planning.
Management:
• Adequate management of Klinefelter syndrome requires a
comprehensive neurodevelopmental evaluation.
• In infancy and early childhood, this often includes a
multidisciplinary approach to determine appropriate
treatments such as physical therapy, infant stimulation
programs, and speech therapy.
• Men with Klinefelter syndrome have congenital
hypogonadism, which results in an inability to produce
normal amounts of testosterone accompanied by an
increase in hypothalamic gonadotrophic hormones.
• Androgen therapy is usually initiated when there is
evidence of a testosterone deficit. Infertility is common in
men with Klinefelter syndrome because of a decreased
sperm count.
• If sperm are present, cryopreservation may be useful for
future family planning. However, genetic counseling is
advised because of the increased risk of autosomal and sex
chromosomal abnormalities.
Summary:
• Genetic disorders can affect a single gene (mendelian
inheritance) or several genes (polygenic inheritance).
• Single-gene disorders may be present on an autosome
or on the X chromosome, and they may be expressed as a
dominant or recessive trait.
• In autosomal dominant disorders, a single mutant
allele from an affected parent is transmitted to an offspring
regardless of sex. The affected parent has a 50% chance of
transmitting the disorder to each offspring.
• Autosomal recessive disorders are manifested only
when both members of the gene pair are affected. Usually,
both parents are unaffected but are carriers of the
defective gene. Their chances of having an affected child
are one in four(25%); of having a carrier child, two in
four(50%); and of having a noncarrier, unaffected child,
one in four (25%).
• Sex-linked disorders, which are associated with the X
chromosome, are those in which an unaffected mother carries
one normal and one mutant allele on the X chromosome.
• She has a 50% chance of transmitting the defective gene to
her sons, who are affected, and her daughters have a 50%
chance of being carriers of the mutant gene.
• Because of a normal paired gene, female heterozygotes rarely
experience the effects of a defective gene.
• The fragile X syndrome is an inherited form of mental
retardation that results from a repeating sequence of three
nucleotides on a single gene in the X chromosome.
• Multifactorial inheritance disorders are caused by multiple
genes and, in many cases, environmental factors.
• Chromosomal disorders result from a change in
chromosome
• number or structure.
• A change in chromosome number is called aneuploidy.
• Monosomy involves the presence of only one member of a
chromosome pair; it is seen in Turner syndrome, in which there
is monosomy of the X chromosome.
• Polysomy refers to the presence of more than two
chromosomes in a set. Klinefelter syndrome involves polysomy
• Trisomy 21(i.e., Down syndrome) is the most common
form of chromosome disorder.
• Alterations in chromosome structure involve deletion
or addition of genetic material, which may involve a
translocation of genetic material from one
chromosome pair to another.