GENETICS

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 Today’s Quranic verse

It is He Who begins (the process of) creation;

then repeats it; and for Him it is most easy.
To Him belongs the loftiest similitude (we can
think of) in the heavens and the earth: for He
is Exalted in Might, full of wisdom. [030:027]

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When you see a person who has been
given more than you in money or beauty,
then look to those who have been given
less.
Mohammed Mustafa (SAWAW)

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•Small minds discuss people…
•Average minds discuss events..
•Great minds discuss ideas..
•Genius silently acts.

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•The completion of the human genome
project has been a landmark event in the
study of human diseases.

•Humans have about 30,000 genes, far

fewer than the 100,000 previously
estimated.

•Powerful technologies now allow

applications of the human gene sequences
to the analysis of human diseases.
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•Until recently the major focus of gene
hunting was on structural genes whose
products encode proteins.

•Recent studies indicate that a very large

number of genes do not encode proteins.
Instead, their products play important
regulatory functions.

•There are about 1000 such genes (3% of

human genome) that encode small RNA
molecules, so-called microRNAs (miRNAs). 7
Generation of micro RNAs and their mode of action
in regulating gene function
 Pri-miRNA
primary microRNA transcript
 Pre-miRNA
precursor microRNA
 RISC
RNA-induced silencing complex.
Dicer
Enzyme generating mature miRNA
by "cutting" pre-miRNA.
• miRNA is 21 to 30 nucleotides
in length
• RISC silence (inhibit) genes
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at a post-transcriptional level.
 Epidemiology
• Genetic disorders are extremely common.

• There is a life-time frequency estimated at 670 per

1000.

• These include cancer and CVS diseases that have

multifactorial genetic components.

• About 20% of the pediatric inpatients in university

hospitals suffer from disorders of genetic origin.

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 Epidemiology
• Chromosomal aberrations have been identified in as
many as 50% of spontaneous abortuses during the
first trimester.

• Many more abortuses probably have gene

mutations.

• Only those mutations compatible with independent

existence constitute the reservoir of genetic disease
in the population at large.

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 Classification of Human Diseases
Human diseases have been classified into three
categories:
Entirely genetically determined

Entirely environmentally determined.

Multifactorial ie those to which both nature and nurture

contribute.
Note: Microbial infections were once thought arising
wholly from environmental influences, but it is now
clear that to a considerable extent, an individual's genetic
makeup influences his or her immune response and
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susceptibility to microbiologic infections.
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 Classification of Human Diseases
• Not all genetic disorders present in infancy and
childhood, and conversely, many pediatric diseases are
not of genetic origin.
• Hereditary disorders are derived from one's parents and
are transmitted in the gametes through generations, and
therefore are familial.
• The term congenital simply implies "present at birth."
• Some congenital diseases are not genetic (e.g.,
congenital syphilis).
• Not all genetic diseases are congenital; Huntington
disease, for example, begins only after the third or fourth
decade of life.
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GENETICS
Scientific study of how physical, biochemical, and behavioral
traits are transmitted from parents to their offspring.
GENE
Gene is a functional unit of heredity composed of DNA, occupying a
specific place (locus) on a chromosome and capable of reproducing
itself exactly at each cell division.
Most of the genes direct the formation of an enzyme or other protein.
GENOME
Total DNA carried by a gamete.
GERM LINE
The cell lineage resulting in formation of eggs or sperm.
LOCUS
It is the site of a specific gene on a chromosome.

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ALLELE
Each gene of the pair is called allele or any one of a series of two or
more different genes that may occupy the same locus on a specific
chromosome. One version of a gene at a given location (locus) along
a chromosome
HOMOLOGUS CHROMOSOME
The chromosomes which pair at meiosis and contain the same set of
gene loci

MOSAICISM
Presence in a person of two different cell lines derived from
a single zygote.

MULTIFACTORIAL DISORDER
Disorder caused by interaction of
more than one gene plus the effect of environment.
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POLYGENIC
HETEROZYGOUS
Person possessing different alleles at a particular locus on the
homologous chromosome

HOMOZYGOUS
Person possessing two identical alleles at a particular focus on
the homologous chromosome

HEMIZYGOUS
Having unpaired genes in an otherwise diploid cell; males are
normally hemizygous for genes on both sex chromosomes.

GENOTYPE
It is the genetic constitution of a person

PHENOTYPE
It is the physical or biochemical characteristics of a person
reflecting genetic constitution & environmental influence
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TRAIT
A genetically determined characteristic or condition recognized
phenotypically.

DOMINANT
Trait expressed in people who are heterozygous for a particular gene.

RECESSIVE
Trait expressed in people who are homozygous / hemizygous but not
in those who are heterozygous for a particular gene.

CO-DOMINANT
Phenotype/trait resulting from full expression of both alleles at a
particular locus in heterozygotes. 17
CARRIER
Healthy persons possessing a (usually harmful) mutant gene in
heterozygous form (also persons with a balanced chromosomal
translocation).

PLEIOTROPISM
Single gene leading to many end effects or the control by a single gene
of several distinct and seemingly unrelated phenotypic effects.

GENETIC HETEROGENEITY
Mutation at several genetic loci producing the same trait.

TRANSLOCATION
Transfer of chromosomal material between two non-homologous
chromosomes.
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PENETRANCE
The frequency, under given environmental conditions, with which a
specific genotype is expressed by an individual.

REDUCED PENETRANCE
Some people inherit the mutant gene but are phenotypically normal-- it
is expressed in mathematical terms.

VARIABLE EXPRESSIVITY
The disorder is seen in all the individuals carrying the mutant gene but
expressed with variable degrees in different individuals.

GENETIC POLYMORPHISM
The occurrence in the same population of multiple discrete allelic
states of which at least two have high frequency (conventionally of 1%
or more).

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Denatured DNA:
single-stranded DNA

Exon:
the portion of the gene that is transcribed into
mRNA, for translation into protein sequences.

Intron:
the rest of the DNA in the gene under discussion.

Gene probe:
a single-stranded nucleic acid sequence, labeled with
radio- isotope or enzyme, used to
identify a specific complementary
sequence

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Southern blotting: using probes to search for particular
DNA sequences, on restriction enzyme digested DNA
fragments which have been separated by electrophoresis.
Invented by Dr. Southern.

Northern blotting: searching for m-RNA by a technique

similar to Southern blotting. Named by some in imitation
of "Southern".

Western blotting: searching for a protein, using

electrophoretic methods

Dot blotting: like Northern and Southern blotting, only

without using gel electrophoresis

In-situ hybridization: using probes to detect nucleic acid

sequences within cells, without destroying the cells 21
themselves.
Calico 22Cat
Calico Cat

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Polymerase chain reaction:
A technique to identify very small quantities (perhaps
even a single copy) of a particular DNA sequence in a
sample.
This has many uses, ranging from the most sensitive and
specific AIDS test to a way of telling whether a leukemia is
completely cured.
Classical genetic research:
Define the biochemical abnormality, then isolate the
protein, sequence it, and identify the gene. How we cloned
the hemoglobin S gene. "Functional cloning."
Reverse genetic research (positional cloning):
It locates the affected chromosome, sequence until you
find the gene, then deduce the protein sequence and find
it, and finally figure out its function.
Duchenne's muscular dystrophy, cystic fibrosis, and Li-
Fraumeni disease were all successfully approached in
this way."Positional cloning." 24
MUTATION

Permanent change in DNA

 Germ line mutations are present in the sperm or ovum.

 Somatic mutations are acquired after fertilization.

 Germ cell mutation is transmitted to progeny and may give rise to

hereditary disease (Vertical transmission)

 Somatic cell mutation do not cause hereditary disease but are

important in genesis of cancer and some congenital malformation
(Horizontal transmission)

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TYPES OF MUTATIONS
Genomic mutation
involves loss or gain of whole chromosome resulting in monosomy /
trisomy

Chromosomal mutation
results from rearrangement of genetic material and gives rise to
visible structural change in chromosome

Gene mutation
results in partial or complete deletion, addition or substitution of
single base

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MUTATION
POINT MUTATIONS
DELETIONS
INSERTIONS

MISSENSE
NONSENSE

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 Some Types of Mutations
Some Types of Mutations

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 Some Types of Mutations
Some Types of Mutations

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Point mutation resulting from a single
base pair change in the DNA.
• A CTC to CAC change
(GAG to GTG in the
opposite strand) leads
to the replacement of
glutamic acid by valine in
the polypeptide chain.
• Substitution of valine for
glutamic acid at the sixth
position of β-chain
produces HbS,
responsible for sickling.
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Point mutation resulting from a single
base pair change in the DNA.
• A CTC to CAC change
(GAG to GTG in the
opposite strand) leads
to the replacement of
glutamic acid by valine in
the polypeptide chain.
• Substitution of valine for
glutamic acid at the sixth
position of β-chain
produces HbS
responsible for sickling.
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Genetic disease:

Almost impossible to define, probably "a disease which is

determined, more or less, the moment the egg is fertilized."

The above definitions of "genetic disease" ignores the other, equally

important, "acquired genetic diseases", i.e., tumors, in which
defective genes are propagated and accumulate within clones of cells
in a single organism.

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Familial disease:

Definitions vary. "Diseases that cluster within families" can include

classic genetic diseases, polygenic disease, heritable viruses,
nutritional stuff, behavioral stuff the child-abuse cycle, obesity.

Congenital disease:

A disease present at birth. Note that sickle cell disease and

Huntington's chorea are both genetic, but are not symptomatic at
birth, and that various traumas and infections acquired in utero are
congenital but not genetic.

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CLASSIFICATION OF GENETIC DISORDERS

 SINGLE GENE DISORDERS WITH CLASSICAL PATTERN OF

INHERITENCE (MENDELIAN DISORDERS)

 SINGLE GENE DISORDERS WITH ATYPICAL PATTERN OF

INHERITENCE

 DISEASES WITH MULTIFACTORIAL INHERITENCE (POLYGENIC)

 CHROMOSOMAL DISORDERS

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 SINGLE GENE DISORDERS WITH CLASSICAL
PATTERN OF INHERITENCE
(MENDELIAN DISORDERS)
Mendelian disorders result from mutations in single genes of large
effect.

• Autosomal Dominant Inheritance.

• Autosomal Recessive Inheritance.
• Co-dominant Inheritance.

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AUTOSOMAL DOMINANT (AD) DISEASES

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 Only one abnormal
copy of the gene
needs to be inherited
for the disease to be
expressed
 Both homozygous
and heterozygous
individuals are
affected.

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AUTOSOMAL DOMINANT (AD) DISEASES
Almost twice as common as autosomal recessive
disorders.

Only one abnormal copy of the paired genes (allele)

is necessary for expression of the disease

Manifests in both homozygous & heterozygous state.

At least one of the parents is usually affected.

Male and females equally affected.

Can be traced through many generation of the family.

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AUTOSOMAL DOMINANT (AD) DISEASES

Affected heterozygous and homozygous parent can

transmit abnormal gene to 50% and 100% offsprings
respectively.

Generally the disorder is not transmitted by the

family members who are not affected.

In many AD diseases, the homozygous genotype is

incompatible with life.

Disorders are transmitted by both sexes

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However,
•In many conditions the age at onset is delayed and
symptoms and signs do not appear until adulthood (as in
Huntington disease).

•Clinical features may be modified by reduced penetrance

& Variable expressivity.

•Non-genetic factors may influence the expression of

dominant genes ie diet in familial hypercholesterolemia
can influence the occurrence of atherosclerosis.

•New mutations may account for the presence of

dominant disorder in subjects with negative family history.

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 BIOCHEMICAL BASIS OF AD DISEASES
Mostly involves quantity or arrangement of large structural proteins,
regulator proteins and receptors, leading to deficiency in proteins
which are in short supply even in health.

Structural proteins:
Marfan's syndrome, Many Ehlers-Danlos variants, Hereditary spherocytosis,
Epidermolysis bullosa , Osteogenesis imperfecta

Receptor/channel problems:
Familial hypercholesterolemia ,The ion channel problems (periodic paralysis
syndromes, myotonia congenital)

Short-supply protein deficiency syndromes:

Von Willebrand's disease, Maturity onset diabetes of the young , Acute
intermittent porphyria

Tumor genes:
Neurofibromatosis I & II, Familial polyposis coli, Multiple endocrine neoplasia
syndrome I, IIa & IIb,
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AUTOSOMAL RECESSIVE (AR) DISEASES
Both copies of the paired gene are required to be abnormal for
expression of the disease.

Manifests itself in homozygotes only.

Male & females are affected equally.

Parents are usually not affected.

Generally there is no family history.

Recurrence rate in future offsprings is 25%.

Often results from consanguineous matings.

Generally appear within a single sib-ship.

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– Offspring of the affected person are healthy heterozygote unless
his/her partner is also carrier

– Onset is frequently in early life, at or shortly after birth

– Expression of defect is more uniform

(if there are several alleles, expressivity may vary)

– Disorders are commonly severe

– New mutations are not uncommon

– Prenatal diagnosis may be possible

– Carriers of most recessive traits can be detected by reduced enzyme

activity or protein migrating abnormally or "restriction fragment
length polymorphism".

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Results in deficiencies or defects of highly specialized proteins
(enzymes, transport proteins), or hemoglobinopathies requiring more
than one dose of a gene

If the autosomal recessive disease is particularly common (worldwide, or in

an ethnic group), it's likely that the heterozygote state confers a significant
advantage on its carrier. Examples: Sickle cell and some other
hemoglobinopathy carriers resist malaria. Cystic fibrosis carriers are much
more resistant to gram-negative intestinal infections.

Deficiencies or defects in highly specialized proteins

Cystic fibrosis ("mucoviscidosis"), Phenylketonuria, Galactosemia,
Adenosine deaminase deficiency (immunodeficiency), alpha1-protease
inhibitor ("antitrypsin") deficiency, Common albinism, Lysosomal storage
diseases (except Fabry's), Most glycogen storage diseases

Major hemoglobin problems

Sickle cell anemia, Hemoglobin C disease, beta-thalassemia major, three and
four-dose alpha-thalassemia syndromes, Combinations of the above

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Autosomal Recessive
inheritance

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X-LINKED DISEASES

– X-linked diseases are those for which the gene is present on the X
chromosome.

– Males and females show different patterns of inheritance and severity

of manifestation.

– There are some characteristics that are common to X-linked

disorders in general. These include:

– X-linked genes are never passed from father to son. The Y

chromosome is the only sex chromosome that passes from father to
son.

– Males are never carriers, if they have a mutated gene on the X

chromosome, it will be expressed.

–Males are termed hemizygous for genes on the X chromosome. 48

X-LINKED RECESSIVE DISORDERS

– Males are much more likely to be affected

– Can be transmitted through healthy female carriers

– Female carrier transmits the disorder to 50% of her sons and 50% of
her daughters will be carrier

– An unaffected male cannot transmit disorder

– An affected male will transmit the mutant gene to all his

daughters but to none of his sons

ABSENCE OF FATHER TO SON TRANSMISSION IS HALLMARK OF X-

LINKED INHERITANCE
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– Affected males generally do not produce as many of these disorders
are severe or lethal during early life

– Occasionally heterozygote female shows some features of the

condition due to non-random X-inactivation

– Homozygous affected state may occour in females

– History of presence of maternally related affected males in different

generations of family is positive

– New mutations are fairly common (family history is not always +)

– Recognition of X-linked disorder is important

– Germline mutations canot be detected

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Examples:

Hemophilia A, Hemophilia, G6PD deficiency Lesch-Nyhan syndrome,

Duchenne's muscular dystrophy, Chronic granulomatous Common red-green
color-blindness, Testicular feminization

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X-linked Recessive
inheritance

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X-LINKED DOMINANT DISORDERS

– Both male & female are affected

– Never passed from father to son
– Affected males produce only affected females.
– Affected females produce 50% normal and 50% affected offspring.
– Males are usually more severely affected than females.
– Females are more likely to be affected.

(fewer males in family than expected but all healthy, excess of females half of
whom are affected)

Examples:
Rickets resistant to vit D, Incontinentia pigmenti, Orofaciodigital syndrome

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X-linked Dominant
inheritance

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Y-LINKED DISORDERS

– Only males are affected

– Transmission from father to son

– Procupine skin, Hairy ears, Webbed toe

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•In codominant inheritance, both alleles are expressed in a
heterozygous person.

•As both alleles at a genetic locus produce some product,

codominance is noticed only if the phenotypes or products of the
alleles are qualitatively different.

•Examples:

•Blood group antigens (eg, AB, MN)

•WBC antigens (eg, DR4, DR3)

•Serum proteins differing in electrophoretic mobility (eg, albumin,

haptoglobulin).

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MULTIFACTORIAL INHERITANCE

This type of inheritance is responsible for both normal phenotypic

variation (i.e. height, weight) among individuals as well as many
common disorders (i.e. neural tube defects, cleft lip and palate) that
are not caused by single genes or chromosomal anomalies.

Traits or disorders that show multifactorial inheritance are affected by

multiple factors that are both genetic and environmental in nature.
Each factor has only a small effect but the cumulative effect of each
results in the phenotype observed.

The term polygenic inheritance is often used interchangeably with

multifactorial. Some, however, reserve polygenic for disorders where
environmental factors are thought not to be involved and the trait is
the result of the interaction of a large number of genes, each with a
small effect on phenotype.
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CHROMOSOMAL DISORDERS

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CYTOGENETICS

The study of chromosomes is referred to as cytogenetics.

Three main tools are used by cytogeneticists to study chromosome

number and structure:

Karyotyping,
Chromosome banding
Fluorescence in situ hybridization (FISH)
Chromosome painting

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KARYOTYPING
Arranging a display of an individual's chromosomes on the basis of length. A
photomicrograph is made of an individual's stained chromosomes and both
copies of each pair are lined up based on banding patterns and the position of
the centromere.

CHROMOSOME BANDING
Chromosomes are enzymatically treated and then stained, resulting in a
characteristic pattern of light and dark bands for each chromosome. Dark
regions are rich in A-T pairs and are relatively inactive. Light regions are less
condensed, transcriptionally active regions that are rich in G-C base pairs. (G-
banding, Q-banding, R-banding)

FISH
A chromosome mapping approach that uses fluorescent tags to detect
hybridization of probes specific for different regions of chromosomes.

CHROMOSOME PAINTING

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Human somatic cell contains 46 chromosomes
22 homologus pairs of autosomes & 2 sex chromosomes XX or XY

Chromosomes take the form of two chromatids connected at

centromere .

Chromosome are divided into 7 groups (A-G) based on their size and
position of centromere.

• Metacenteric---centromere is in center
• Submetacenteric--centromere is off center
• Acrocentric--- centromere is near end

Each chromosome has short (p) & long arm (q)

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• Three basic shapes and the
component parts of human
metaphase chromosomes.
• The relative size of the
satellite on the acrocentric
is exaggerated for
visibility.
• Chromosomes13, 14, 15,
21 & 22 have small masses
of chromatin called
satellites which form the
nucleolus of an interphase
nucleus.
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• A banded karyotype of
the X-chromosome.
• Arms, regions, bands and
sub-bands are shown.
• The approximate
locations of some genetic
errors are indicated.
• Xp22.2 refers to sub-band
2, band 2, region 2 of the
short arm (p) of the
X-chromosome.

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CHROMOSOMAL ABNORMALITIES
(CYTOGENETIC DISORDERS)

NUMERICAL ABNORMALITIES

Haploid:Number of chromosomes in gametes after meiotic division (n)

Diploid is 2n (number of chromosomes in normal somatic cell)

Polyploid: any other exact multiple of n (3n, 4n, 5n---)

(can arise due to errors in meiosis during gamete formation, problems during
fertilization, or errors in mitosis during early stages of embryo formation.

Aneuploid
Any chromosome number which is not exact multiple of haploid
number (n). In humans, this is most often due to the gain or loss of a
single chromosome.

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 During chiasma formation, one
of the two sister chromatids on
one chromosome pairs with one
of the chromatids of the
homologous chromosome.
 Genetic recombination occurs
through crossing-over and
results in recombinant and
nonrecombinant chromosome
segments in the gametes.
 Together with the random
segregation of the maternal and
paternal chromosomes,
recombination contributes to
genetic diversity and forms the
basis of the concept of linkage.

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Causes

Non-disjunction

When homologus pair of chromosome fails to disjoin at first meiotic

division or 2 chromatids fail to separate either at second meiotic
division or in somatic cell division (mitosis)

During gametogenesis it will result in two gametes n+1 & n-1 & if each
is fertilized by a normal gamete the end result will be

2n+1 (trisomy) & 2n-1 (monosomy)

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Anaphase lag

One chromosome in meiosis or one chromatid in mitosis lags behind

and is left out of the nucleus.

During gametogenesis it will results in two gametes one n & other n-1
and if each is fertilized by a normal gamete the end result will be 2n
(normal cell) & 2n-1(monosomy)

•Monosomy & trisomy involving sex chromosomes is compatible with

life and is associated with variable degree of phenotypic abnormalities
[Monosomy X (Turner's syndrome), XXY (Klinefelter syndrome), XXX syndrome, XYY
syndrome]

•Autosomal monosomy is incompatible with life

•Autosomal trisomy do permit survival in trisomy 13, 18, and 21

Advanced maternal age is a pre-disposing factor in these

aneuploidies. 77
DOWN SYNDROME
It is the most common cause of chromosomal disorders and a major
cause of mental retardation.

Incidence: 1: 700
Karyotypes: Trisomy 21 (95%) 47,XX, + 21
Translocation (04%) 46XX,der(14:21) +21
Mosaic type (01%) 46,XX/47,XX, +21

• 40% have congenital heart disease

• More prone to acute leukemia (10-20 fold increased risk)
• Above 40 year of age almost all show evidence of Alzheimer
disease

• Have abnormal immune system and more prone to serious

infections 78
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 MOLECULAR BASIS OF DOWN SYNDROME
• Little is known about the molecular basis of Down
syndrome.
• Approximately 300 genes have been found on
chromosome21, 16 being involved in mitochondrial
energy pathway, several others likely influence CNS
and a group is involved in folate metabolism.
• How each of these groups is related to DS is unclear.
• Likely the extra copy of chromosome 21 shuts down
certain genes due to abnormal feedback mechanisms or
causes overexpression of some genes.
• There is a global upregulation of chromosome 21 gene
expression in the Down syndrome brain. 80
Trisomy 18 (Edwards Syndrome)
Incidence: 1: 8000
Karyotypes: Trisomy 18 47,XX, + 18
Mosaic type 46,XX/47,XX, +18

Most affected are female; generally lethal in males, death by age 2-3
severe mental retardation
very small nose, mouth, receding chin
no distal flexion creases in fingers
severe organ malformations

Trisomy 13 (Patau syndrome)

Incidence: 1: 6000
Karyotypes: Trisomy 13 47,XX, + 13
Translocation 46XX, -14, +t(14q13q)
Mosaic type 46,XX/47,XX, +13

Severe mental retardation, heart and organ defects, polydactyly

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death by the age of one year
Cri-du-Chat Syndrome
Karyotype: 46 XX or XY, 5p-

Wailing, cat-like cry in about 50% of those afflicted, microcephaly, severe

mental retardation, heart and other organ deformities, essentially, this is a
partial monosomy.

Prader-Willi Syndrome
Short stature, obesity, small extremities, poor muscle tone, mental
retardation, insatiable appetite (non-functioning satiety feedback
mechanisms) probably responsible for the obesity, caused by the deletion
of a specific region of chromosome 15.
Unusual expression of this disease is due to a phenomenon known as
"parental imprinting" .

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X-Inactivation, Imprinting, and Uniparental Disomy
The same genetic mutation or chromosome abnormality can
have a different effect in the individual depending on which
parent provided the altered gene or chromosome.
For example, two different syndromes are associated with the
deletion of a particular section of one of chromosomes 15.
If the deletion-containing chromosome is inherited from the
father, the child will be short, obese, and mildly mentally
retarded (Prader-Willi syndrome).
If the deletion is from the mother, the child will be of normal
height, thin, severely mentally retarded, subject to seizures, and
lacking in muscular coordination (Angelman syndrome).
This is due to genetic imprinting.

According to traditional Mendelian principles, the parental origin of a

mutant gene is irrelevant for the expression of the phenotype. There are
important exceptions to this rule. 83
X-inactivation prevents the expression of most genes on one of the two
X-Inactivation, Imprinting, and Uniparental Disomy
Prader-Willi syndrome:
Characterized by diminished fetal activity, obesity, hypotonia, mental
retardation, short stature, and hypogonadism.
Deletions in the Prader-Willi syndrome occur exclusively on the
paternal chromosome 15.
In contrast, patients with Angelman syndrome, characterized by mental
retardation, seizures, ataxia, and hypotonia, have deletions at the same
site of chromosome 15; however, they are located on the maternal
chromosome 15.
These two syndromes may also result from uniparental disomy. In this
case, the syndromes are not caused by deletions on chromosome 15 but
by the inheritance of either two paternal chromosomes (Prader-Willi
syndrome), or two maternal chromosomes (Angelman syndrome).

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• In generation I, male A has
inherited, mutant allele from his
affected mother (not shown);
the gene is "turned off" during
spermatogenesis, and therefore
none of his offspring
(generation II) will express the
mutant allele, regardless if they
are carriers. Howe the gene will
be "turned on" again during
oogenesis in any of his
daughters B who inherit the
allele. All offspring (generation
III) who inherit the mutant
allele will be affected. All
offspring of normal children C
will produce normal offspring.
Children of female D will all
express the mutation if they
inherit the allele. 88
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TURNER SYNDROME

The syndrome represents a wide spectrum of clinical presentation, the most

common of which is the classic Turner's Syndrome with 45 XO karyotype,
less common the Mosaic Turner's Syndrome with Mosaic sex chromosome
Karyotypes 45X/46XX, 45X/46XY.

Classically it is characterized by short stature, gonadal dysgenesis,

amenorrhea and lymphedema

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KLINEFELTER SYNDROME

Klinefelter syndrome is the most common chromosomal disorder associated

with male hypogonadism and infertility. It is defined classically by a 47, XXY
karyotype with variants demonstrating additional X and Y chromosomes.

Some variations include 46XY/47XXY mosaicism; 48XXXY 48XXYY; and

46XX males, which is termed sex-reversal syndrome

The syndrome is characterized by hypogonadism (small testes,

azoospermia/oligospermia), gynecomastia at late puberty, psychosocial
problems, hyalinization and fibrosis of the seminiferous tubules, and
elevated urinary gonadotropins.

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Fragile X syndrome (Martin-Bell syndrome)

Some chromosomes (including X chromosome) have what is termed "fragile" sites

which are susceptible to breakage, at least in vitro, when subjected to insufficient
concentrations of certain chemicals such as folic acid. Some of these regions are
thus called "folate sensitive" sites.

This syndrome, the Fragile X syndrome, is the most common inherited form of
mental retardation.

This trait is dominant: a heterozygous female may express the mental retardation,
though only about 30% of those affected express the mental retardation (variable
penetrance). The trait is not fully expressed in all individuals. (variable expressivity)
About 80% of affected males express mental retardation.

Physical traits: long, narrow face w/ protruding chin, large ears, large testicles.
The responsible gene is FMR-1 (product of this gene is expressed in the brain.
The gene consists of many trinucleotide repeats.
normal - 50 repeats; carrier - 50 - 200 repeats; expressor - 200 or more repeats.

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STRUCTURAL ABNORMALITIES

Abnormalities in chromosome structure follow a chromosome break and,

during the repair process, the reunion of the wrong segments
of the chromosome.

If, following repair, there is a loss or gain of chromosomal material (an

unbalanced rearrangement) there can be significant clinical consequences.

If there is no loss or gain of chromosomal material (a balanced

rearrangement), then the individual is mentally and physically normal.

However, there is an increased risk of having chromosomally abnormal

offspring because individuals who carry balanced chromosome
rearrangements may produce chromosomally unbalanced gametes. They are
also more likely to have miscarriages and may be identified if a chromosome
study is done to determine the cause of the pregnancy losses.

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STRUCTURAL ABNORMALITIES

Deletion

It is loss of part of a chromosome, either "terminal" (46XY del

(16)(p14) or "interstitial" (11 p-Wilm’s tumor)

Translocation

A segment of one chromosome is transferred to another

Balanced reciprocal translocation:

There are single breaks in each of two chromosomes with mutual

exchange of genetic material 46 XX, t (2;5) (q31;p14), no loss of
genetic material and phenotypically normal but there is increased risk
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of abnormal gametes & unbalanced zygotes
"Robertsonian translocation":

It is a reciprocal translocation involving two acrocentric chromosomes,

(13, 14, 15, 21 or 22) producing a tiny chromosome which is lost and a
very large chromosome, compatible with normal phenotype however
gamete formation is abnormal.

Isochromosome

It result from faulty chromosome division. The products are a

chromosome with two long arms, and a chromosome with two short
arms. i(Xq)

Duplications

It refers to an extra chromosomal segment within the same

homologous chromosome or an extra chromosomal segment on
another non-homologous chromosome. Again, the clinical findings are
highly variable depending upon the chromosomal segments 99
involved.
Inversion

It is rearrangement that involve two breaks in the same chromosome,

with the reincorporation of inverted segments.

Paracentric involves one arm of the chromosome and in pericentric

breaks are in opposite side of centromere, perfectly compatible with
normal development

Ring chromosomes

It results from deletions at both ends of a chromosome, with

subsequent fusion of their ends. Obviously, this chromosome is not
going to take a normal role in mitosis.

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LYONIZATION

Inactivation, at or about 16th day of embryogenesis, of all but one of

the X-chromosomes in each cell.

Inactivation of either the maternal or paternal X chromosome occurs at

random

Once lyonization has occurred, the same X-chromosome will be

inactivated in all of that cell's progeny, where it will be the Barr body (or
bodies, for those with more than two X's), or sex chromatin (visible on
buccal smear), until oogenesis is required again.

Most of the normal females are mosaic & have two population of cells
one with inactivated maternal and the other with inactivated paternal X

Not the entire chromosome is not inactivated.

Inactivated X chromosome is selectively activated in germ cells before

the first meiotic division 116
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MOSAICISM
Presence in a person of two or more than two different cell lines
derived from a single zygote due to mitotic errors in early
development during cleavage of fertilized ovum or in somatic cells.

Mosaicism affecting sex chromosome is relatively common like

mosaic varient of Turner syndrome 45X/47XXX or 46XX/45X/47XXX.
Repeated mitotic errors may lead to many populations of cells.
Phenotypic expression is dependant on the number & distribution of
abnormal cells (45x).

Autosomal mosaicism appears to be much less common.

An error in early mitotic division affecting the autosomes usually lead

to non-viable mosaic with autosomal monosomy.

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CHIMERISM

It arises from the mixing of cells from two individuals usually blood
from twins during intrauterine life and is cytogenetically
indistinguishable from mosaicism

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FIGURE 6-11 Three basic shapes and the component parts of human
metaphase chromosomes. The relative size of the satellite on the
acrocentric is exaggerated for visibility. (Adapted from Cormack
D.H. [1993]. Essential histology. Philadelphia: J.B. Lippincott)
example, Xp22.2 refers to subband 2, band 2, region 2« the short arm
(p) of the X chromosome.
In summary, the genetic information in a cell is org nized, stored, and
retrieved as small cellular structur called chromosomes. Forty-six
chromosomes arrange in 23 pairs are present in the human being.
Twent two of these pairs are autosomes. The 23rd pair is tl sex
chromosomes, which determine the sex of a p* son. Two types of cell
division occur, meiosis and n tosis. Meiosis is limited to replicating
germ cells ai results in the formation of gametes or reproducti cells
(ovum and sperm), each of which has only a si gle set of 23
chromosomes. Mitotic division occurs somatic cells and results in the
formation of 23 pa of chromosomes. A karyotype is a photograph oi
person's chromosomes. It is prepared by special la oratory techniques
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