Dna mutation

DNA MUTATION
MADE BY - GIREESHA SHARMA

Defining the term “Mutation”, what it
is?
• Mutation is a natural process that changes a DNA
sequence. And it is more common than you may think.
As a cell copies its DNA before dividing, a "typo" occurs
every 100,000 or so nucleotides. That's about 120,000
typos each time one of our cells divides.
• Most commonly, a single base is substituted for
another. Sometimes a base is deleted or an extra base
is added. Fortunately, the cell is able to repair most of
these changes. When a DNA change remains
unrepaired in a cell that will become an egg or a
sperm, it is passed down to offspring. Thanks to
mutation, we all have some new variations that were
not present in our parents.

• People commonly use the terms "mutant" and mutation"
to describe something undesirable or broken. But mutation
is not always bad. Most DNA changes fall in the large areas
of the genome that sit between genes, and usually they
have no effect. When variations occur within genes, there is
more often a consequence, but even then mutation only
rarely causes death or disease. Mutation also generates
new variations that can give an individual a survival
advantage. And most often, mutation gives rise to
variations that are neither good nor bad, just different.
• Mutation is a permanent change in the DNA. Mutation in
germ cells are transmissible, in somatic cells its non -
transmissible but may contribute to change (malignant
transformations). Changes in the nucleotide sequence of
the DNA, may occur in somatic cells aren’t passed to
offspring, may occur in gametes and passed to offspring. It
happens regularly, almost all mutations are natural.
Chemicals and UV radiations cause them. Many mutations
are repaired by enzymes.

CHAPTER – 1
TYPES OF MUTATION
• Where do mutations occur?
• Mutations can be grouped into two main categories based on where they
occur: somatic mutations and germ-line mutations.
• Somatic mutations take place in non-reproductive cells. Many kinds of
somatic mutations have no obvious effect on an organism, because
genetically normal body cells are able to compensate for the mutated
cells. Nonetheless, certain other mutations can greatly impact the life and
function of an organism. For example, somatic mutations that affect cell
division (particularly those that allow cells to divide uncontrollably) are
the basis for many forms of cancer.
• Germ-line mutations occur in gametes or in cells that eventually produce
gametes. In contrast with somatic mutations, germ-line mutations are
passed on to an organism's progeny. As a result, future generations of
organisms will carry the mutation in all of their cells (both somatic and
germ-line).

• What kinds of mutations exist?
• Mutations aren't just grouped according to where they
occur — frequently, they are also categorized by the length
of the nucleotide sequences they affect.
•
• Changes to short stretches of nucleotides are called gene-
level mutations, because these mutations affect the
specific genes that provide instructions for various
functional molecules, including proteins. Changes in these
molecules can have an impact on any number of an
organism's physical characteristics. As opposed to gene-
level mutations, mutations that alter longer stretches of
DNA (ranging from multiple genes up to entire
chromosomes) are called chromosomal mutations. These
mutations often have serious consequences for affected
organisms. Because gene-level mutations are more
common than chromosomal mutations, the following
sections focus on these smaller alterations to the normal
genetic sequence.

• Base substitution
• Base substitutions are the simplest type of gene-level mutation,
and they involve the swapping of one nucleotide for another during
DNA replication. For example, during replication, a thymine
nucleotide might be inserted in place of a guanine nucleotide. With
base substitution mutations, only a single nucleotide within a gene
sequence is changed, so only one codon is affected. Although a
base substitution alters only a single codon in a gene, it can still
have a significant impact on protein production. In fact, depending
on the nature of the codon change, base substitutions can lead to
three different subcategories of mutations. The first of these
subcategories consists of missense mutations, in which the altered
codon leads to insertion of an incorrect amino acid into a protein
molecule during translation; the second consists of nonsense
mutations, in which the altered codon prematurely terminates
synthesis of a protein molecule; and the third consists of silent
mutations, in which the altered codon codes for the same amino
acid as the unaltered codon.

TYPES OF MUTATION
• Small-scale mutations, such as those affecting a small gene in one or
a few nucleotides, including:
• Point mutations, often caused by chemicals or malfunction of DNA
replication, exchange a single nucleotide for another. These changes are
classified as transitions or transversions. Most common is
the transition that exchanges a purine for a purine (A ↔ G) or
a pyrimidine for a pyrimidine, (C ↔ T). A transition can be caused by
nitrous acid, base mis-pairing, or mutagenic base analogs such as 5-
bromo-2-deoxyuridine (BrdU). Less common is a transversion, which
exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔
A/G). An example of a transversion is the conversion of adenine (A) into
a cytosine (C). A point mutation can be reversed by another point
mutation, in which the nucleotide is changed back to its original state
(true reversion) or by second-site reversion (a complementary mutation
elsewhere that results in regained gene functionality). Point mutations
that occur within the protein coding region of a gene may be classified
into three kinds, depending upon what the erroneous codon codes for:
– Silent mutations, which code for the same (or a sufficiently similar) amino
acid.
– Missense mutations, which code for a different amino acid.
– Nonsense mutations, which code for a stop and can truncate the protein.
•

• Insertions and deletions
• Insertions and deletions are two other types of
mutations that can affect cells at the gene level.
An insertion mutation occurs when an extra
nucleotide is added to the DNA strand during
replication. This can happen when the replicating
strand "slips," or wrinkles, which allows the extra
nucleotide to be incorporated .
• Strand slippage can also lead to deletion
mutations. A deletion mutation occurs when a
wrinkle forms on the DNA template strand and
subsequently causes a nucleotide to be omitted
from the replicated strand.

INSERTION AND
DELETION METHOD-

• Large-scale
mutationsin chromosomal structure,
including:
– Amplifications (or gene duplications) leading to
multiple copies of all chromosomal regions, increasing
the dosage of the genes located within them.
– Deletions of large chromosomal regions, leading to
loss of the genes within those regions.
– Mutations whose effect is to juxtapose previously
separate pieces of DNA, potentially bringing together
separate genes to form functionally distinct fusion
genes (e.g., bcr-abl). These include:
• Chromosomal translocations: interchange of genetic parts
from nonhomologous chromosomes.

• Interstitial deletions: an intra-chromosomal deletion
that removes a segment of DNA from a single
chromosome, thereby apposing previously distant
genes. For example, cells isolated from a
human astrocytoma, a type of brain tumor, were found
to have a chromosomal deletion removing sequences
between the "fused in glioblastoma" (fig) gene and the
receptor tyrosine kinase "ros", producing a fusion
protein (FIG-ROS). The abnormal FIG-ROS fusion
protein has constitutively active kinase activity that
causes oncogenic transformation (a transformation
from normal cells to cancer cells).
• Chromosomal inversions: reversing the orientation of a
chromosomal segment.

– Loss of heterozygosity: loss of one allele, either by
a deletion or a recombination event, in an
organism that previously had two different alleles.

• Frameshift mutations
• Insertion or deletion of one or more nucleotides during
replication can also lead to another type of mutation
known as a frameshift mutation. The outcome of a
frameshift mutation is complete alteration of the
amino acid sequence of a protein. This alteration
occurs during translation because ribosome’s read the
mRNA strand in terms of codons, or groups of three
nucleotides. These groups are called the reading frame.
Thus, if the number of bases removed from or inserted
into a segment of DNA is not a multiple of three, the
reading frame transcribed to the mRNA will be
completely changed. Consequently, once it encounters
the mutation, the ribosome will read the mRNA
sequence differently, which can result in the
production of an entirely different sequence of amino
acids in the growing polypeptide chain.

• To better understand frameshift mutations, let's consider the
analogy of words as codons, and letters within those words as
nucleotides. Each word itself has a separate meaning, as each
codon represents one amino acid. The following sentence is
composed entirely of three-letter words, each representing a three-
letter codon:
• THE BIG BAD FLY HAD ONE RED EYE AND ONE BLU EYE.
• Now, suppose that a mutation eliminates the sixth nucleotide, in
this case the letter "G". This deletion means that the letters shift,
and the rest of the sentence contains entirely new "words":
• THE BIB ADF LYH ADO NER EDE YEA NDO NEB LUE YE.
• This error changes the relationship of all nucleotides to each codon,
and effectively changes every single codon in the sequence.
Consequently, there is a widespread change in the amino acid
sequence of the protein. Lets consider an example with an RNA
sequence that codes for a sequence of amino acids:
• AUG AAA CUU CGC AGG AUG AUG AUG

• With the triplet code, the sequence shown in
figure 5 corresponds to a protein made of the
following amino acids:
Methionine-Lysine-Leucine-Arginine-Arginine-
Methionine-Methionine-Methionin

• Now, suppose that a mutation occurs during replication, and it
results in deletion of the fourth nucleotide in the sequence.
When separated into triplet codons, the nucleotide sequence
would now read as follows.
AUG AAC UUC GCA GGA UGA UGA UG
This series of codons would encode the following sequence of
amino acids:
Methionine-Asparagine-Phenylalanine-Alanine-Glycine-STOP-
STOP

• Each of the stop codons tells the ribosome to terminate protein
synthesis at that point. Consequently, the mutant protein is entirely
different due to the deletion of the fourth nucleotide, and it is also
shorter due to the appearance of a premature stop codon. This
mutant protein will be unable to perform its necessary function in
the cell.
• What causes mutations?
• Mutations can arise in cells of all types as a result of a variety of
factors, including chance. In fact, some of the mutations discussed
above are the result of spontaneous events during replication, and
they are thus known as spontaneous mutations. Slippage of the
DNA template strand and subsequent insertion of an extra
nucleotide is one example of a spontaneous mutation; excess
flexibility of the DNA strand and the subsequent mispairing of bases
is another.
• Environmental exposure to certain chemicals, ultraviolet radiation,
or other external factors can also cause DNA to change. These
external agents of genetic change are called mutagens. Exposure to
mutagens often causes alterations in the molecular structure of
nucleotides, ultimately causing substitutions, insertions, and
deletions in the DNA sequence.

• What are the consequences of mutations?
• Mutations are a source of genetic diversity in
populations, and, as mentioned previously, they can
have widely varying individual effects. In some cases,
mutations prove beneficial to an organism by making it
better able to adapt to environmental factors. In other
situations, mutations are harmful to an organism — for
instance; they might lead to increased susceptibility to
illness or disease. In still other circumstances,
mutations are neutral, proving neither beneficial nor
detrimental outcomes to an organism. Thus, it is safe
to say that the ultimate effects of mutations are as
widely varied as the types of mutations themselves.

• Mutation generates new alleles -
• The whole human family is one species with the same genes.
Mutation creates slightly different versions of the same genes,
called alleles. These small differences in DNA sequence make every
individual unique. They account for the variation we see in human
hair color, skin color, height, shape, behavior, and susceptibility to
disease. Individuals in other species vary too, in both physical
appearance and behavior.
• Genetic variation is useful because it helps populations change over
time. Variations that help an organism survive and reproduce are
passed on to the next generation. Variations that hinder survival
and reproduction are eliminated from the population. This process
of natural selection can lead to significant changes in the
appearance, behavior, or physiology of individuals in a population,
in just a few generations.
• Once new alleles arise, meiosis and sexual reproduction combine
different alleles in new ways to increase genetic variation.

• Mutation VS Variation –
• It's useful to think of mutation as a process that creates genetic
variation. We often refer to a mutation as a thing—the genetic
variation itself. This approach can be useful when it comes to a
gene associated with a disease: the disease allele carries a
mutation, a DNA change that compromises the protein's function.
However, this approach gives mutation a bad name.
• It’s important to remember that losing the function of a gene
doesn’t always affect health. For example, most mammals have
hundreds of genes that code for olfactory receptors, proteins that
help us smell. Losing one of these genes probably doesn’t make all
that much difference.
• In contrast to variations that cause disease, there are many more
examples of variations that are neither good nor bad, but just
different—like blood types and eye color. Just like with disease
alleles, the process of mutation creates these more neutral
variations. But with neutral variations, it can be impossible to tell
which allele is the "normal" one that existed first and which is the
"mutant"—and the distinction is often meaningless.

• Proteins and Switches – Mutation creates variations in protein-
coding portions of genes that can affect the protein itself. But even
more often, it creates variations in the "switches" that control when
and where a protein is active and how much protein is made.
• Lactase is an enzyme that helps infants break down lactose, a sugar
in milk. Normally the gene that codes for lactase is active in babies
and then turned off at about age four. When people who don't
make lactase consume milk, they experience gas, nausea, and
discomfort. But some people have a variation in a genetic switch
that keeps the lactase gene active. This variation is called "lactase
persistence," and people who have it can keep milk in their diets
even as adults.
• Other drivers of mutation – Environment factors:
• Radiation, chemicals, byproducts of cellular metabolism, free
radicals, ultraviolet rays from the sun—these agents damage
thousands of nucleotides in each of our cells every day. They affect
the nucleotides themselves: converting one base to another,
knocking a base off its backbone, or even causing a break in the
DNA strand.

• DNA Repair - Most of the time, mutation is reversed. DNA
repair machines are constantly at work in our cells, fixing
mismatched nucleotides and splicing broken DNA strands
back together. Yet some DNA changes remain. If a cell
accumulates too many changes—if its DNA is so damaged
that repair machinery cannot fix it—it either stops dividing
or it self-destructs. If any of these processes go wrong, the
cell could become cancerous.
• When we put on sun screen, we are protecting ourselves
against mutation in somatic cells—the cells that make up
the body and are not involved in reproduction. Only when
DNA changes are carried in egg and sperm cells are they
passed to the next generation. Believe it or not, a certain
amount of sloppiness is built into the system. Without
mutation there would be no variation, and without
variation there would be no evolution.

• Nomenclature
• In order to categorize a mutation as such, the "normal" sequence
must be obtained from the DNA of a "normal" or "healthy"
organism (as opposed to a "mutant" or "sick" one), it should be
identified and reported; ideally, it should be made publicly available
for a straightforward nucleotide-by-nucleotide comparison, and
agreed upon by the scientific community or by a group of expert
geneticists and biologists, who have the responsibility of
establishing the standard or so-called "consensus" sequence. This
step requires a tremendous scientific effort. (See DNA sequencing.)
Once the consensus sequence is known, the mutations in a genome
can be pinpointed, described, and classified. The committee of the
Human Genome Variation Society (HGVS) has developed the
standard human sequence variant nomenclature, which should be
used by researchers and DNA diagnostic centers to generate
unambiguous mutation descriptions. In principle, this nomenclature
can also be used to describe mutations in other organisms. The
nomenclature specifies the type of mutation and base or amino
acid changes.

• Nucleotide substitution (e.g., 76A>T) — The
number is the position of the nucleotide from the
5' end; the first letter represents the wild type
nucleotide, and the second letter represents the
nucleotide that replaced the wild type. In the
given example, the adenine at the 76th position
was replaced by a thymine.
– If it becomes necessary to differentiate between
mutations in genomic DNA, mitochondrial DNA, and
RNA, a simple convention is used. For example, if the
100th base of a nucleotide sequence mutated from G
to C, then it would be written as g.100G>C if the
mutation occurred in genomic DNA, m.100G>C if the
mutation occurred in mitochondrial DNA, or r.100g>c
if the mutation occurred in RNA. Note that, for
mutations in RNA, the nucleotide code is written in
lower case.

• Amino acid substitution (e.g., D111E) — The first
letter is the one letter code of the wild type
amino acid, the number is the position of the
amino acid from the N-terminus, and the second
letter is the one letter code of the amino acid
present in the mutation. Nonsense mutations are
represented with an X for the second amino acid
(e.g. D111X).
• Amino acid deletion (e.g., ΔF508) — The Greek
letter Δ (delta) indicates a deletion. The letter
refers to the amino acid present in the wild type
and the number is the position from the N
terminus of the amino acid were it to be present
as in the wild type.

• Contribution of mutations
• The contribution of mutations is different in the tissues. This may
be due to different mutation rates by cell division and the different
number of cell divisions in each tissue.
• Furthermore, knowing the mutational processes, mutation rates
and the process of tissue development, can show the history of
individual cells. For that, used cellular genome sequencing.
• Mutation rates
• Mutation rates vary across species. Evolutionary biologist have
theorized that higher mutation rates are beneficial in some
situations, because they allow organisms to evolve and therefore
adapt more quickly to their environments. For example, repeated
exposure of bacteria to antibiotics, and selection of resistant
mutants, can result in the selection of bacteria that have a much
higher mutation rate than the original population (mutator strains).
• According to one study, two children of different parents had 35
and 49 new mutations. Of them, in one case 92% were from the
paternal germline, in another case, 64% were from the maternal
germline.

• Harmful mutations
• Changes in DNA caused by mutation can cause errors
in protein sequence, creating partially or completely non-functional
proteins. Each cell, in order to function correctly, depends on
thousands of proteins to function in the right places at the right
times. When a mutation alters a protein that plays a critical role in
the body, a medical condition can result. A condition caused by
mutations in one or more genes is called a genetic disorder. Some
mutations alter a gene's DNA base sequence but do not change the
function of the protein made by the gene. One study on the
comparison of genes between different species
of Drosophila suggests that if a mutation does change a protein, this
will probably be harmful, with an estimated 70 percent of amino
acid polymorphisms having damaging effects, and the remainder
being either neutral or weakly beneficial.Studies have shown that
only 7% of point mutations in non-coding DNA of yeast are
deleterious and 12% in coding DNA are deleterious. The rest of the
mutations are either neutral or slightly beneficial.

• If a mutation is present in a germ cell, it can give rise to offspring that
carries the mutation in all of its cells. This is the case in hereditary
diseases. In particular, if there is a mutation in a DNA repair gene within a
germ cell, humans carrying such germ-line mutations may have an
increased risk of cancer. A list of 34 such germ-line mutations is given in
the article DNA repair-deficiency disorder.
• An example of one is albinism. A mutation that occurs in the OCA1 or
OCA2 gene. Individuals with this disorder are more prone to many types of
cancers, other disorders and have impaired vision. On the other hand, a
mutation may occur in a somatic cell of an organism. Such mutations will
be present in all descendants of this cell within the same organism, and
certain mutations can cause the cell to become malignant, and, thus,
cause cancer.
• A DNA damage can cause an error when the DNA is replicated, and this
error of replication can cause a gene mutation that, in turn, could cause a
genetic disorder. DNA damages are repaired by the DNA repair system of
the cell. Each cell has a number of pathways through which enzymes
recognize and repair damages in DNA. Because DNA can be damaged in
many ways, the process of DNA repair is an important way in which the
body protects itself from disease. Once a DNA damage has given rise to a
mutation, the mutation cannot be repaired. DNA repair pathways can only
recognize and act on "abnormal" structures in the DNA. Once a mutation
occurs in a gene sequence it then has normal DNA structure and cannot
be repaired.

• Beneficial mutations
• Although mutations that cause changes in protein sequences can be
harmful to an organism, on occasions the effect may be positive in a
given environment. In this case, the mutation may enable the
mutant organism to withstand particular environmental stresses
better than wild-type organisms, or reproduce more quickly. In
these cases a mutation will tend to become more common in a
population through natural selection.
• For example, a specific 32 base pair deletion in human CCR5 (CCR5-
Δ32) confers HIV resistance to homozygotes and delays AIDS onset
in heterozygotes. One possible explanation of the etiology of the
relatively high frequency of CCR5-Δ32 in the European population is
that it conferred resistance to the bubonic plague in mid-14th
century Europe. People with this mutation were more likely to
survive infection; thus its frequency in the population
increased. This theory could explain why this mutation is not found
in southern Africa, which remained untouched by bubonic plague. A
newer theory suggests that the selective pressure on the CCR5
Delta 32 mutation was caused by smallpoxinstead of the bubonic
plague.

• Another example is Sickle-cell disease, a blood disorder
in which the body produces an abnormal type of the
oxygen-carrying substance hemoglobin in the red
blood cells. One-third of all indigenous inhabitants
of Sub-Saharan Africa carry the gene,because, in areas
where malaria is common, there is a survival value in
carrying only a single sickle-cell gene (sickle-cell
trait). Those with only one of the two alleles of the
sickle-cell disease are more resistant to malaria, since
the infestation of the malaria plasmodium is halted by
the sickling of the cells that it infests.
• Prion mutations
• Prions are proteins and do not contain genetic
material. However, prion replication has been shown to
be subject to mutation and natural selection just like
other forms of replication.

• Somatic mutations
• Main article: Loss of heterozygosity
• See also: Carcinogenesis
• A change in the genetic structure that is not inherited from a
parent, and also not passed to offspring, is called a somatic cell
genetic mutation or acquired mutation.
• When analyzing somatic mutations present in the cells of
multicellular organisms, can know its origin and its past.
• Cells with heterozygous mutations (one good copy of gene and one
mutated copy) may function normally with the unmutated copy
until the good copy has been spontaneously somatically mutated.
This kind of mutation happens all the time in living organisms, but it
is difficult to measure the rate. Measuring this rate is important in
predicting the rate at which people may develop cancer.
• Point mutations may arise from spontaneous mutations that occur
during DNA replication. The rate of mutation may be increased
by mutagens. Mutagens can be physical, such as radiation from UV
rays, X-rays or extreme heat, or chemical (molecules that misplace
base pairs or disrupt the helical shape of DNA). Mutagens
associated with cancers are often studied to learn about cancer and
its prevention.

• Gain-of-function research
• The aim of gain-of-function (GOF) research is
to genetically engineer increased transmissibility,
virulence, or host range of pathogens. As such, it has
been extremely controversial. As a Nature editorial put
it in October 2014, "revelations over the past few
months of serious violations and accidents at some of
the leading bio safety containment labs in the United
States has burst the hubris that some scientists, and
their institutions, have in their perceived ability to
work safely with dangerous pathogens."There is a
current moratorium on such work in the United States.

CHAPTER – 2
Mutation Related Diseases
• DNA is constantly subject to mutations, accidental changes
in its code. Mutations can lead to missing or malformed
proteins, and that can lead to disease.
• We all start out our lives with some mutations. These
mutations inherited from your parents are called germ-line
mutations. However, you can also acquire mutations during
your lifetime. Some mutations happen during cell division,
when DNA gets duplicated. Still other mutations are caused
when DNA gets damaged by environmental factors,
including UV radiation, chemicals, and viruses.
• Few mutations are bad for you. In fact, some mutations can
be beneficial. Over time, genetic mutations create genetic
diversity, which keeps populations healthy. Many mutations
have no effect at all. These are called silent mutations.

• But the mutations we hear about most often are the ones that cause
disease. Some well-known inherited genetic disorders include cystic
fibrosis, sickle cell anemia, Tay-Sachs disease, phenylketonuria and color-
blindness, among many others. All of these disorders are caused by the
mutation of a single gene.
• Most inherited genetic diseases are recessive, which means that a person
must inherit two copies of the mutated gene to inherit a disorder. This is
one reason that marriage between close relatives is discouraged; two
genetically similar adults are more likely to give a child two copies of a
defective gene.
• Diseases caused by just one copy of a defective gene, such as Huntington's
disease, are rare. Thanks to natural selection, these dominant genetic
diseases tend to get weeded out of populations over time, because
afflicted carriers are more likely to die before reproducing.
• Scientists estimate that every one of us has between 5 and 10 potentially
deadly mutations in our genes-the good news is that because there's
usually only one copy of the bad gene, these diseases don't manifest.
• Cancer usually results from a series of mutations within a single cell.
Often, a faulty, damaged, or missing p53 gene is to blame. The p53 gene
makes a protein that stops mutated cells from dividing. Without this
protein, cells divide unchecked and become tumors.

• Sickle Cell
• These are the sickle-shaped blood cells of someone with sickle cell
anemia, a genetic disease common among those of African descent.
• Sickle cell anemia is the result of a point mutation, a change in just
one nucleotide in the gene for hemoglobin. This mutation causes
the hemoglobin in red blood cells to distort to a sickle shape when
deoxygenated. The sickle-shaped blood cells clog in the capillaries,
cutting off circulation.
• Having two copies of the mutated genes cause sickle cell anemia,
but having just one copy does not, and can actually protect against
malaria - an example of how mutations are sometimes beneficial.
•

• Heart and Muscle Disease
• One basic mutation in mitochondrial DNA has been suggested as a
cause for heart and muscle disease. All human cells have
mitochondria and they also hold DNA. Mitochondria produce
energy through the metabolism of calories that you consume from
food along with the oxygen you inhale.
• In this process, mitochondria also create oxygen radicals, which can
harm the mitochondrial DNA, resulting in a greater number of
mutations in body tissues. Unlike a cell's DNA, mitochondrial DNA is
found around the cell's nucleus. It is also inherited only from the
mother. It is when mitochondrial DNA damage builds up - typically
associated with ageing - the body no longer produces energy as
effectively and efficiently. Tissue and organ deterioration follows
and disease may occur. Unfortunately, the energy metabolism of
mitochondria make them particularly susceptible to mutations.
With improved understanding of mitochondrial DNA mutations,
however, we can pave the way for new treatments for heart and
muscle disease.

• Breast and Ovarian Cancer
• Our knowledge that breast and ovarian cancer is caused by genetic
factors in a small percentage of the population is not new
information but our discoveries of specific genetic mutations have
occurred more recently - over the past two decades. In the mid
1990s, it was found that the gene BRCA1, when mutated,
significantly raised a person's odds of developing breast cancer.
Shortly thereafter, another gene known as BRCA2 was identified,
which also has been found to raise a person's risk of breast cancer.
• Researchers now are aware that any mutations in these two genes
can also raise a person's risk of ovarian cancer. In fact, this risk is
higher for individuals of Ashkenazi Jewish background. Research has
also shown that BRCA1 mutations may increase the risk of other
cancers such as colon or prostate. Mutations in the BRCA2 gene are
suggested to increase the risk of other cancers such as those of the
pancreas or prostate. More studies are being performed now to
investigate any possible links between these two genes and other
forms of cancer such as skin or lung cancer.

• Alzheimer's Disease
• Alzheimer's disease tends to run in families, which means
that if a person in your family suffers from the disease, your
risk of developing the disease is higher than the general
population. One reason for this elevated risk is due to
mutations within genes in your DNA. Researchers have now
identified a handful of genes that play a role in the
development of early-onset Alzheimer's disease but they
have yet to conclusively identify a gene that triggers late-
onset Alzheimer's disease. The inherited genes that have
been identified include APP, presenilin-1 and presenilin-2.
Due to the dominant inheritance of these three genes, you
only need to inherit a single copy of the gene mutation for
development of the disease. The relationship to early-onset
Alzheimer's disease means that those who do inherit a
mutated form of the gene are likely to develop Alzheimer's
disease prior to age sixty-five.

• Angelman syndrome is a neuro -genetic
disorder characterized by severe intellectual and
developmental disability, sleep disturbance, seizures, jerky
movements (especially hand-flapping), frequent laughter or
smiling, and usually a happy demeanor.
• AS is a classic example of genomic imprinting in that it is
caused by deletion or inactivation of genes on the
maternally inherited chromosome 15 while the paternal
copy, which may be of normal sequence, is imprinted and
therefore silenced. The sister syndrome, Prader-Willi
syndrome, is caused by a similar loss of paternally inherited
genes and maternal imprinting.
• AS is named after a British pediatrician, Harry Angelman,
who first described the syndrome in 1965.[1] An older,
alternative term for AS, "happy puppet syndrome", is
generally considered pejorative and stigmatizing so it is no
longer the accepted term. People with AS are sometimes
referred to as "angels", both because of the syndrome's
name and because of their youthful, happy appearance.

• There is currently no cure available. The epilepsy can be
controlled by the use of one or more types
of anticonvulsant medications. However, there are
difficulties in ascertaining the levels and types of
anticonvulsant medications needed to establish control,
because AS is usually associated with having multiple
varieties of seizures, rather than just the one as in normal
cases of epilepsy. Many families use melatonin to promote
sleep in a condition which often affects sleep patterns.
Many individuals with Angelman syndrome sleep for a
maximum of 5 hours at any one time. Mild laxatives are
also used frequently to encourage regular bowel
movements, and early intervention with physiotherapy is
important to encourage joint mobility and prevent
stiffening of the joints. Speech and Language Therapy is
commonly employed to assist individuals with Angelman
syndrome and their communication issues.

Those with the syndrome are
generally happy and contented
people who like human contact
and play. People with AS exhibit a
profound desire for personal
interaction with others.
Communication can be difficult at
first, but as a child with AS
develops, there is a definite
character and ability to make
themselves understood.
People with AS tend to develop strong
non-verbal skills to compensate for their
limited use of speech. It is widely
accepted that their understanding of
communication directed to them is
much larger than their ability to return
conversation. Most afflicted people will
not develop more than 5–10 words, if
any at all. Seizures are a consequence,
but so is excessive laughter, which is a
major hindrance to early diagnosis.

• Color blindness, is the inability or decreased ability to see color, or perceive color
differences, under normal lighting conditions. Color blindness affects a significant
percentage of the population.There is no actual blindness but there is a deficiency
of color vision. The most usual cause is a fault in the development of one or more
sets of retinal cones that perceive color in light and transmit that information to
the optic nerve. This type of color blindness is usually a sex-linked condition. The
genes that produce photopigments are carried on the X chromosome; if some of
these genes are missing or damaged, color blindness will be expressed in males
with a higher probability than in females because males only have one X
chromosome (in females, a functional gene on only one of the two X
chromosomes is sufficient to yield the needed photopigments).
• Color blindness can also be produced by physical or chemical damage to the eye,
the optic nerve, or parts of the brain. For example, people
with achromatopsia suffer from a completely different disorder, but are
nevertheless unable to see colors.
• The first scientific paper on this subject, Extraordinary facts relating to the vision of
colours, was published by the English chemist John Dalton in 1798 after the
realization of his own color blindness. Because of Dalton's work, the general
condition has been called daltonism, although in English this term is now used only
for deuteranopia.

Color blindness is usually classified as a mild disability, however there are
occasional circumstances where it can give an advantage. Some studies
conclude that color blind people are better at penetrating certain color
camouflages. Such findings may give an evolutionary reason for the high
prevalence of red–green color blindness. There is also a study suggesting that
people with some types of color blindness can distinguish colors that people
with normal color vision are not able to distinguish.

• There is generally no treatment to cure color
deficiencies. ″The American Optometric Association
reports a contact lens on one eye can increase the
ability to differentiate between colors, though nothing
can make you truly see the deficient
color.″ Optometrists can supply colored spectacle
lenses or a single red-tint contact lens to wear on the
non-dominant eye, but although this may improve
discrimination of some colors, it can make other colors
more difficult to distinguish. A 1981 review of various
studies to evaluate the effect of the X-chromosome
contact lens concluded that, while the lens may allow
the wearer to achieve a better score on certain color
vision tests, it did not correct color vision in the natural
environment.

• Cystic fibrosis (CF), also known as mucoviscidosis, is a genetic
disorder that affects mostly the lungs but also
the pancreas, liver,kidneys and intestine. Long-term issues
include difficulty breathing and coughing up sputum as a result of
frequent lung infections. Other symptoms include sinus
infections, poor growth, fatty stool, clubbing of the finger and toes,
and infertility in males among others. Different people may have
different degrees of symptoms.
• CF is an autosomal recessive disorder. It is caused by the presence
of mutations in both copies of the gene for the protein cystic
fibrosis transmembrane conductance regulator (CFTR).Those with a
single working copy are carriers and otherwise mostly normal.CFTR
is involved in production of sweat, digestive fluids,
and mucus.[4] When not functional usually thin secretions become
thick. The condition is diagnosed by a sweat test and genetic
testing. Screening of infants at birth takes place in some areas of
the world.

There is no cure for cystic fibrosis. Lung infections are treated with antibiotics which
may be given intravenously, inhaled, or by mouth. Sometimes the
antibiotic azithromycin is used long term. Inhaled hypertonic
saline and salbutamol may also be useful. Lung transplantation may be an option if
lung function continues to worsen. Pancreatic enzyme replacement and fat soluble
vitamin supplementation are important, especially in the young. While not well
supported by evidence, many people use airway clearance techniques such as chest
physiotherapy.[1] The average life expectancy is between 37 and 50 years in
the developed world.[6] Lung problems are responsible for death in 80% of people.

• CF is most common among people of Northern European ancestry and affects about one out
of every three thousand newborns.About one in twenty five are carriers. It is least common
in Africans and Asians. It was first recognized as a specific disease by Dorothy Andersen in
1938, with descriptions that fit the condition occurring at least as far back as 1595.The
name cystic fibrosis refers to the characteristic fibrosis and cysts that form within
the pancreas.
• While there are no cures for cystic fibrosis, there are several treatment methods. The
management of cystic fibrosis has improved significantly over the past 70 years. While infants
born with cystic fibrosis 70 years ago would have been unlikely to live beyond their first year,
infants today are likely to live well into adulthood. Recent advances in the treatment of cystic
fibrosis have meant that an individual with cystic fibrosis can live a fuller life less encumbered
by their condition. The cornerstones of management are proactive treatment of airway
infection, and encouragement of good nutrition and an active lifestyle. Pulmonary
rehabilitation as a management of cystic fibrosis continues throughout a person's life, and is
aimed at maximizing organ function, and therefore quality of life. At best, current treatments
delay the decline in organ function. Because of the wide variation in disease symptoms,
treatment typically occurs at specialist multidisciplinary centers, and is tailored to the
individual. Targets for therapy are the lungs, gastrointestinal tract (including pancreatic
enzyme supplements), the reproductive organs (including assisted reproductive
technology (ART)) and psychological support.
• The most consistent aspect of therapy in cystic fibrosis is limiting and treating the lung
damage caused by thick mucus and infection, with the goal of maintaining quality of life.
Intravenous, inhaled, and oral antibiotics are used to treat chronic and acute infections.
Mechanical devices and inhalation medications are used to alter and clear the thickened
mucus. These therapies, while effective , can be extremely time consuming too.

• Down syndrome also known as trisomy 21, is a genetic
disorder caused by the presence of all or part of a third
copy of chromosome 21. It is typically associated
with physical growth delays, characteristic facial
features, and mild to moderate intellectual
disability. The average IQ of a young adult with Down
syndrome is 50, equivalent to the mental age of an 8-
or 9-year-old child, but this varies widely.
• Down syndrome can be identified during pregnancy
by prenatal screening followed by diagnostic testing, or
after birth by direct observation and genetic testing.
Since the introduction of screening, pregnancies with
the diagnosis are often terminated.Regular screening
for health problems common in Down syndrome is
recommended throughout the person's life.

• Education and proper care have been shown to improve quality of
life. Some children with Down syndrome are educated in typical
school classes, while others require more specialized education.
Some individuals with Down syndrome graduate from high school
and a few attend post-secondary education. In adulthood, about
20% in the United States do paid work in some capacity with many
requiring a sheltered work environment. Support in financial and
legal matters is often needed. Life expectancy is around 50 to
60 years in the developed world with proper health care.
• Down syndrome is the most common chromosome abnormality in
humans, occurring in about one per 1000 babies born each year. In
2013 it resulted in 36,000 deaths down from 43,000 deaths in 1990.
It is named after John Langdon Down, the British doctor who fully
described the syndrome in 1866. Some aspects of the condition
were described earlier by Jean-Étienne Dominique Esquirol in 1838
and Édouard Séguin in 1844. The genetic cause of Down
syndrome—an extra copy of chromosome 21—was identified by
French researchers in 1959.

• Hemophilia - is a group of hereditary genetic disorders that impair the
body's ability to control blood clotting, which is used to stop bleeding
when a blood vessel is broken. Haemophilia A (clotting factor
VIII deficiency) is the most common form of the disorder, present in about
1 in 5,000–10,000 male births. Haemophilia B (factor IX deficiency) occurs
in around 1 in about 20,000–34,000 male births.
• Like most recessive sex-linked, X chromosome disorders, haemophilia is
more likely to occur in males than females. This is because females have
two X chromosomes while males have only one, so the defective gene is
guaranteed to manifest in any male who carries it. Because females have
two X chromosomes and haemophilia is rare, the chance of a female
having two defective copies of the gene is very remote, so females are
almost exclusively asymptomatic carriers of the disorder.
• Female carriers can inherit the defective gene from either their mother or
father, or it may be a new mutation. Although it is not impossible for a
female to have haemophilia, it is unusual: daughters which are the
product of both a male with hemophilia A or B and a female carrier will
have haemophilia, while the non-sex-linked haemophilia C due to
coagulant factor XI deficiency, which can affect either sex, is more
common in Jews of Ashkenazi (east European) descent but rare in other
population groups.

• Haemophilia patients have lower clotting factor level
of blood plasma or impaired activity of the coagulation
factors needed for a normal clotting process. Thus
when a blood vessel is injured, a temporary scab does
form, but the missing coagulation factors
prevent fibrin formation, which is necessary to
maintain the blood clot. A haemophiliac does not
bleed more intensely than a person without it, but can
bleed for a much longer time. In severe haemophiliacs
even a minor injury can result in blood loss lasting days
or weeks, or even never healing completely. In areas
such as the brain or inside joints, this can be fatal or
permanently debilitating.

• Though there is no cure for haemophilia, it can be controlled with regular
infusions of the deficient clotting factor, i.e. factor VIII in haemophilia A or
factor IX in haemophilia B. Factor replacement can be either isolated from
human blood serum, recombinant, or a combination of the two. Some
haemophiliacs develop antibodies (inhibitors) against the replacement
factors given to them, so the amount of the factor has to be increased or
non-human replacement products must be given, such as porcine factor
VIII.
• If a patient becomes refractory to replacement coagulation factor as a
result of circulating inhibitors, this may be partially overcome with
recombinant human factor VII (NovoSeven), which is registered for this
indication in many countries.

• Klinefelter syndrome is the set of symptoms that result from two or
more X chromosome in males.The primary feature is sterility. Often
symptoms may be subtle and many people do not realize they are
affected. Sometimes symptoms are more prominent and may include
weaker muscles, greater height, poor coordination, less body hair,
smaller genitals, breast growth, and less interest in sex. Often it is only
at puberty that these symptoms are noticed. Intelligence is usually
normal; however, reading difficulties and problems with speech are more
common. Symptoms are typically more severe if three or more X
chromosomes are present.
• Klinefelter syndrome usually occurs randomly. An older mother might
increase the risk slightly. The condition is not inherited from one's
parents.The underlying mechanisms involves at least one extra X
chromosome in addition to a Y chromosome such that there is a total of
47 or more chromosomes rather than usual 46. KS is diagnosed by
the genetic test known as a karyotype.
• While there is no cure a number of treatments may help. Physical
therapy, speech and language therapy, counselling, and adjustments of
teaching methods may be useful. Testosterone replacement may be used
in those who have significantly low levels. Enlarged breasts may be
removed by surgery. About half of males affected with the help of assisted
reproductive technology have a chance of having children; however, this is
expensive and carries risks. The condition has a nearly normal life
expectancy.

• Klinefelter syndrome is the most
common chromosomal disorder, and it occurs in 1:500
to 1:1000 live male births. It is named after Harry
Klinefelter who identified the condition in the 1940s. In
1956 it was determined to be due to an extra X
chromesome.Mice also can have the XXY syndrome,
making them a useful research model.
• The genetic variation is irreversible. Often individuals
that have noticeable breast tissue
or hypogonadism experience depression and/or social
anxiety because they are outside of social norms. This
is academically referred to
as psychosocial morbidity. At least one study indicates
that planned and timed support should be provided for
young men with Klinefelter syndrome to ameliorate
current poor psychosocial outcomes.

• Phenylketonuria is an inborn error of metabolism involving
impaired metabolism of phenylalanine, one of the amino acids.
Phenylketonuria is caused by absent or virtually
absent phenylalanine hydroxylase (PAH) enzyme activity.
• Protein-rich foods or the sweetener aspartame can act as poisons
for people with phenylketonuria. The role of PAH is to break down
excess phenylalanine from food. Phenylalanine is a necessary part
of the human diet and is naturally present in all kinds of dietary
protein. It is also used to make aspartame, known by the trade
name Nutrasweet, which is used to sweeten low-calorie and sugar
free soft drinks, yogurts, and desserts. In people without PKU, the
PAH enzyme breaks down any excess phenylalanine from these
sources beyond what is needed by the body. However, if there is
not enough of the PAH enzyme or its cofactor, then phenylalanine
can build up in the blood and brain to toxic levels, affecting brain
development and function. PKU is rare, but important to identify,
because if caught early it is very treatable. It is not contagious, and
it is lifelong, but with early diagnosis and consistent treatment, the
damaging effects can be minimal or non-existent.

• Untreated PKU can lead to intellectual disability, seizures, and other serious
medical problems. The best proven treatment for classical PKU patients is a strict
phenylalanine-restricted diet supplemented by a medical formula containing
amino acids and other nutrients. In the United States, the current
recommendation is that the PKU diet should be maintained for life. Patients who
are diagnosed early and maintain a strict diet can have a normal life span with
normal mental development.
• PKU is an inherited disease. When an infant is diagnosed with PKU, it is never the
result of any action of the parents or any environmental factor. Rather, for a child
to inherit PKU, both of his or her parents must have at least one mutated allele of
the PAH gene. Most parents who are carriers of PKU genes are not aware that they
have this mutation because being a carrier causes no medical problems. To be
affected by PKU, a child must inherit two mutated alleles, one from each parent.
PKU is not curable. However, if PKU is diagnosed early enough, an affected
newborn can grow up with normal brain development and live a normal life in
terms of educational achievement, career success, etc., by managing and
controlling phenylalanine ("Phe") levels through diet, or a combination of diet and
medication.
• When Phe cannot be metabolized by the body, a typical diet that would be healthy
for people without PKU causes abnormally high levels of Phe to accumulate in the
blood, which is toxic to the brain. If left untreated, complications of PKU include
severe intellectual disability, brain function abnormalities, microcephaly, mood
disorders, irregular motor functioning, and behavioral problems such as attention
deficit hyperactivity disorder, as well as physical symptoms such as a "musty" odor,
eczema, and unusually light skin and hair coloration. In contrast, PKU patients who
follow the prescribed dietary treatment from birth, may have no symptoms at all.
Their PKU would be detectable only by a blood test.

• To achieve these good outcomes, all PKU patients must adhere to a
special diet low in Phe for optimal brain development. Since Phe is
necessary for the synthesis of many proteins, it is required for
appropriate growth, but levels must be strictly controlled in PKU
patients.
• PKU is not a food allergy or a digestive problem. Eating "forbidden"
foods does not cause an immediate reaction. The phenylalanine
from that food remains in the person's system, however, and as Phe
accumulates over time they may experience concentration and
mood problems, as well as eczema and other symptoms. For
children, developmental problems may occur if levels are elevated
frequently or remain elevated for a significant amount of time.
• Optimal health ranges (or "target ranges") are between 120 and
360 µmol/L or equivalently 2 to 6 mg/dL, and aimed to be achieved
during at least the first 10 years, to allow the brain to develop
normally.

• Sickle-cell disease (SCD), is a hereditary blood disorder,
characterized by an abnormality in the oxygen-
carrying haemoglobin molecule in red blood cells. This leads to a
propensity for the cells to assume an abnormal, rigid, sickle-like
shape under certain circumstances. Sickle-cell disease is associated
with a number of acute and chronic health problems, such as
severe infections, attacks of severe pain ("sickle-cell crisis"),
and stroke, and there is an increased risk of death.
• Sickle-cell disease occurs when a person inherits two abnormal
copies of the haemoglobin gene, one from each parent. Several
subtypes exist, depending on the exact mutation in each
haemoglobin gene. A person with a single abnormal copy does not
experience symptoms and is said to have sickle-cell trait. Such
people are also referred to as carriers.
• The complications of sickle-cell disease can be prevented to a large
extent with vaccination, preventive antibiotics, blood transfusion,
and the drug hydroxyurea/hydroxycarbamide. A small proportion
requires a transplant of bone marrow cells.

• Almost 300,000 children are born with a form of sickle-
cell disease every year, mostly in sub-Saharan Africa,
but also in other parts of the world such as the West
Indies and in people of African origin elsewhere in the
world. In 2013 it resulted in 176,000 deaths up from
113,000 deaths in 1990.The condition was first
described in the medical literature by the American
physician James B. Herrick in 1910, and in the 1940s
and 1950s contributions by Nobel prize-winner Linus
Pauling made it the first disease where the exact
genetic and molecular defect was elucidated.
• Folic acid and penicillin
•

Children born with sickle-cell disease undergo close observation by the pediatrician and require
management by a haematologist to assure they remain healthy. These patients take a 1 mg dose
of folic acid daily for life. From birth to five years of age, they also have to take penicillin daily due
to the immature immune system that makes them more prone to early childhood illnesses.

• Malaria chemoprophylaxis
• The protective effect of sickle-cell trait does not apply to people with
sickle cell disease; in fact, they are more vulnerable to malaria, since the
most common cause of painful crises in malarial countries is infection with
malaria. It has therefore been recommended that people with sickle-cell
disease living in malarial countries should receive anti-malarial
chemoprophylaxis for life.

Vaso-occlusive crisis
• Most people with sickle-cell disease have intensely
painful episodes called vaso-occlusive crises. However,
the frequency, severity, and duration of these crises
vary tremendously. Painful crises are treated
symptomatically with pain medications; pain
management requires opioid administration at regular
intervals until the crisis has settled. For milder crises, a
subgroup of patients manage on NSAIDs (such
as diclofenac or naproxen). For more severe crises,
most patients require inpatient management for
intravenous opioids; patient-controlled analgesia (PCA)
devices are commonly used in this
setting. Diphenhydramine is also an effective agent
that doctors frequently prescribe to help control
itching associated with the use of opioids.

• Acute chest crisis
• Management is similar to vaso-occlusive crisis, with the
addition of antibiotics (usually a quinolone or
macrolide, since cell wall-deficient ["atypical"] bacteria
are thought to contribute to the syndrome), oxygen
supplementation for hypoxia, and close observation.
Should the pulmonary infiltrate worsen or the oxygen
requirements increase, simpleblood
transfusion or exchange transfusion is indicated. The
latter involves the exchange of a significant portion of
the patients red cell mass for normal red cells, which
decreases the percent of haemoglobin S in the
patient's blood. The patient with suspected acute chest
syndrome should be admitted to the hospital with
worsening A-a gradient an indication for ICU admission.

• Hydroxyurea
• The first approved drug for the causative treatment of
sickle-cell anaemia, hydroxyurea, was shown to
decrease the number and severity of attacks in a study
in 1995 (Characheet al.) and shown to possibly
increase survival time in a study in 2003 (Steinberg et
al.). This is achieved, in part, by reactivating fetal
haemoglobin production in place of the haemoglobin S
that causes sickle-cell anaemia. Hydroxyurea had
previously been used as a chemotherapy agent, and
there is some concern that long-term use may be
harmful, but this risk has been shown to be either
absent or very small and it is likely that the benefits
outweigh the risks.

• Transfusion therapy
• Blood transfusions are often used in the management of sickle-cell disease
in acute cases and to prevent complications by decreasing the number of
red blood cells (RBC) that can sickle by adding normal red blood cells.In
children prophylactic chronic red blood cell (RBC) transfusion therapy has
been shown to be efficacious to a certain extent in reducing the risk of
first stroke or silent stroke when transcranial
Doppler (TCD) ultrasonography shows abnormal increased cerebral blood
flow velocities. In those who have sustained a prior stroke event it also
reduces the risk of recurrent stroke and additional silent strokes.
• Bone marrow transplants
• Bone marrow transplants have proven effective in children. Bone marrow
transplants are the only known cure for SCD. However, bone marrow
transplants are difficult to obtain because of the specific HLA typing
necessary. Ideally, a twin family member (syngeneic) or close relative
(allogeneic) would donate the bone marrow necessary for transplantation.

• Tay–Sachs disease is a rare autosomal recessive genetic disorder. In its most
common variant (known as infantile Tay–Sachs disease), it causes a progressive
deterioration of nerve cells and of mental and physical abilities that begins around
six months of age and usually results in death by the age of four. The disease
occurs when harmful quantities of cell membrane components known
as gangliosides accumulate in the brain's nerve cells, eventually leading to the
premature death of the cells. A ganglioside is a form of sphingolipid, which makes
Tay–Sachs disease a member of the sphingolipidoses. There is no known cure or
treatment.
• The disease is named after the British ophthalmologist Waren Tay, who in 1881
first described a symptomatic red spot on the retina of the eye; and after the
American neurologist Bernard Sachs of Mount Sinai Hospital, New York, who
described in 1887 the cellular changes of Tay–Sachs disease and noted an
increased disease prevalence in Ashkenazi Jewish people. Research in the late 20th
century demonstrated that Tay–Sachs disease is caused by a genetic mutation in
the HEXA gene on (human) chromosome 15.
• A large number of HEXA mutations have been discovered, and new ones are still
being reported. These mutations reach significant frequencies in specific
populations. French Canadians of southeastern Quebec have a carrier frequency
similar to that seen in Ashkenazi Jews, but carry a different mutation. Cajuns of
southern Louisiana carry the same mutation that is seen most commonly in
Ashkenazi Jews.

• HEXA mutations are rare and are most seen in genetically isolated populations.
Tay–Sachs can occur from the inheritance of either two similar, or two unrelated,
causative mutations in the HEXA gene.
• As an autosomal recessive disorder, two Tay–Sachs alleles are required for an
individual to exhibit symptoms of the disease. Carriers of a single Tay–Sachs allele
do not exhibit symptoms of the disease but appear to be protected to some extent
against tuberculosis. This accounts for the persistence of the allele in certain
populations in that it confers a selective advantage—in other words, being
a heterozygote is advantageous.
• There is currently no cure or treatment for Tay–Sachs disease. Even with the best
care, children with infantile Tay–Sachs disease die by the age of 4. Although
experimental work is underway, no current medical treatment of the root cause
yet exists. Patients receive supportive care to ease the symptoms or extend
life. Infants are given feeding tubes when they can no longer swallow.
Improvements in life-extending care have somewhat lengthened the survival of
children with Tay–Sachs disease, but no current therapy is able to reverse or delay
the disease's progress.
• In late-onset Tay-Sachs, medication (e.g., lithium for depression) can sometimes
control psychiatric symptoms and seizures, although some medications
(e.g., tricyclic antidepressants, phenothiazines, haloperidol, and risperidone) are
associated with significant adverse effects. In 2011, researchers discovered
that Pyrimethamine can increase ß-hexosaminidase activity, thus slowing down
the progression of Late-Onset Tay–Sachs disease.

• Turner syndrome (TS) is a condition in which a femaleis partly or
completely missing an X chromosome. Signs and symptoms vary
among those affected. Often there is a short and webbed
neck, low-set ears, low hairline at the back of the neck, short
stature, and swollen hands and feet at birth. Typically they
arewithout menstrual periods, do not develop breasts, and
are unable to have children. Heart defects, diabetes, and low
thyroid hormone occur more frequently. Most people with TS have
normal intelligence. Many, however, have troubles with spatial
visualization such as that needed for mathematics. Vision and
hearing problems occur more often.
• Turner syndrome is not usually inherited from a person's
parents. There are no known environmental risks and the mother's
age does not play a role. Turner syndrome is due to a chromosomal
abnormality in which all or part of one of the X chromosomes is
missing or altered. While most people have 46 chromosomes,
people with TS usually only have 45. The chromosomal abnormality
may be present in just some cells in which case it is known as TS
with mosaicism. In these cases the symptoms are usually fewer and
possibly there are none at all. Diagnosis is based on physical signs
and genetic testing

• There is no cure for Turner syndrome. Treatment, however, may help with
symptoms. Human growth hormone injections during childhood may
increase adult height. Estrogen replacement therapy can promote
development of the breasts and hips. Medical care is often required to
manage other health problems with which TS is associated.
• Turner syndrome occurs in between 1 in 2000 to 1 in 5000 females at
birth. All regions of the world and cultures are affected about equally.
People with TS have a shorter life expectancy, mostly due to heart
problems and diabetes. Henry Turner first described the condition in 1938.
In 1964 it was determined to be due to a chromosomal abnormality.
• As a chromosomal condition, there is no cure for Turner syndrome.
However, much can be done to minimize the symptoms. For example:
• Doctors might use a shot of a growth hormone known as Genotropin
(Pfizer)
• Growth hormone, either alone or with a low dose of androgen, will
increase growth and probably final adult height. Growth hormone is
approved by the U.S. Food and Drug Administration for treatment of
Turner syndrome and is covered by many insurance plans. There is
evidence that this is effective, even in toddlers.

• Estrogen replacement therapy such as the birth control pill, has
been used since the condition was described in 1938 to promote
development of secondary sexual characteristics. Estrogens are
crucial for maintaining good bone integrity, cardiovascular health
and tissue health. Women with Turner Syndrome who do not have
spontaneous puberty and who are not treated with estrogen are at
high risk for osteoporosis and heart conditions.
• Modern reproductive technologies have also been used to
help women with Turner syndrome become pregnant if
they desire. For example, a donor egg can be used to create
an embryo, which is carried by the Turner syndrome
woman.
• Uterine maturity is positively associated with years of
estrogen use, history of spontaneous menarche, and
negatively associated with the lack of current hormone
replacement therapy.

CHAPTER -3
DETECTION OF DNA MUTATION
• There are few mutation detection method
present in our labs which I am going to discuses
here.
Genetic disorders are traditionally categorized into
three main groups: single-gene, chromosomal,
and multifactorial disorders.
• Single gene or Mendelian disorders result from
errors in DNA sequence of a gene and include
autosomal dominant (AD), autosomal recessive
(AR), X-linked recessive (XR), X-linked dominant
and Y-linked (holandric) disorders.

• Chromosomal disorders are due to chromosomal
aberrations including numerical and structural
damages. Molecular and cytogenetic techniques
have been applied to identify genetic mutations
leading to diseases. Accurate diagnosis of diseases is
essential for appropriate treatment of patients,
genetic counseling and prevention strategies.
Characteristic features of patterns of inheritance are
briefly reviewed and a short description of
chromosomal disorders is also presented. A
combination of genes and environmental factors is
involved in multifactorial disorders such as
congenital heart disease, most types of cleft
lip/palate, club foot, and neural tube defects If the
DNA sequence is mutated and the alteration is not
repaired by the cell, subsequent replications
reproduce the mutation.

• A variety of mechanisms can cause mutations
ranging from a single nucleotide alteration to
the loss, duplication or rearrangement of
chromosomes.
• Mendelian Disorders
• Gregor Mendel discovered a set of principles
of heredity in the mid-19th century;
characteristic patterns of inheritance are
determined on the basis of these principles.
Single gene disorders arising from errors in
DNA sequence of a gene are categorized into
autosomal dominant (AD), autosomal
recessive (AR), X-linked recessive (XR), X-linked
dominant and Y-linked (holandric) disorders.

• In autosomal dominant disorders , damage in one allele of a pair of
the gene leads to the deficiency , e.g. a mutation in FGFR3 gene can
cause achondroplasia . A parent with an autosomal dominant
disorder has a 50% chance of transmitting the disease to her/his
child. The range of signs and symptoms of some diseases in
different people vary widely (variable expressivity), e.g.
• some people with Marfan syndrome (due to mutation in FBN1)
have only mild symptoms (such as being tall and thin with long,
slender fingers), while others have life-threatening complications
involving the heart and blood vessels as well. Furthermore, some
individuals exhibit signs and symptoms of a given disorder while
others do not, even though they have the disease-causing mutation
(i.e. a proportion of people with a particular mutation show the
condition in this type of disorders), e.g. many people having
mutation of the BRCA1 gene will develop breast cancer during their
lifetime, while some people will not. In other words, in a pedigree a
healthy individual has at least one affected parent and one affected
child (skipped generation) .

• Mutations in both alleles (loss of function) of a gene
are required to cause the defect to appear in an
autosomal recessive disorder, i.e. an affected person
has got one abnormal allele from one heterozygous
parent. In this type of disorders, there is a 25% chance
of having an affected offspring for heterozygous
parents. In case of common autosomal recessive
disorders or traits (sickle cell anemia due to a specific
mutation in HBB gene encoding beta globin or
nonsyndromic autosomal recessive hearing loss due to
mutations in GJB2 gene encoding connexin 26),
sometimes a homozygous affected person marries a
heterozygous carrier; such an example, in which
apparently dominant transmission of this disorder
occurs, is called pseudodominant inheritance.

• In an X-linked disorder , the mutated gene is
located on the X chromosome. A recessive
mutation can lead to the disease. The gene in
chromosome X should be mutated to cause
the condition; hence, an X-linked recessive
disorder is carried by females, while usally
affects males.
• Some of genetic conditions follow none of the
mentioned patterns of inheritance;
mitochondrial diseases, trinucleotide
expansion disorders and genomic imprinting
defects have non-Mendelian or nontraditional
pattern of inheritance

• Chromosomal Disorders
• Typically, somatic cells proliferate via division called mitosis while germ
cells are produced through meiosis division. Meiosis involves a
reductional division followed by an equational division, Meiosis I and II,
respectively.
• Oogenesis begins in the female fetus at 12 weeks, but it is stopped in a
stage of meiosis I (when the homologous chromosomes have
replicated and paired as bivalents or tetrads) at about 20 weeks. At
puberty usually only one oocyte is released per month; a primary
oocyte completes meiosis I and produces one secondary oocyte and
one polar body. Chromosomal aberrations including numerical (due to
errors at chromosome pairing and crossing-over) and structural
damages lead to chromosomal disorders . Aneuploidy is usually due to
failure of segregation of chromosomes in meiosis I or meiosis II (non-
disjunction, premature disjunction or anaphase lag) ; examples of
numerical aberrations include Down syndrome (trisomy 21), Edwards
syndrome (trisomy 18), Patau syndrome (trisomy 13), Klinefelter
syndrome (XXY syndrome), Turner syndrome (monosomy X) and
trisomy X. Chromosomal errors in oocytes are increased dramatically
with maternal age. Non-disjunction or chromosome lag during mitosis
can lead to mosaicism

• With the development of new technologies for more
accurate understanding of the genome and potential gene
therapies, the detection of mutations has an increasingly
central role in various areas of genetic diagnosis including
preimplantation genetic diagnosis (PGD), prenatal diagnosis
(PND), presymptomatic testing, confirmational diagnosis
and forensic/identity testing. Two groups of tests,
molecular and cytogenetic, are used in genetic syndromes.
In general, single base pair mutations are identified by
direct sequencing, DNA hybridization and/or restriction
enzyme digestion methods. However, there are two
approaches for genetic diagnosis; indirect approach
depends on the results from a genetic linkage analysis using
DNA markers such as STR(short tandem repeat) or VNTR
(variable number tandem repeat) markers flanking or
within the gene. The direct approach for diagnosis
essentially depends on the detection of the genetic
variations responsible for the disease.

• Cytogenetics and Molecular Cytogenetics
• Conventional Karyotyping: Chromosome
studies are advised in the following situations:
suspected chromosome abnormality, sexual
disorders, multiple congenital anomalies
and/or developmental retardation,
undiagnosed learning disabilities, infertility or
multiple miscarriage, stillbirth and
malignancies. Traditionally, the microscopic
study of chromosomes is performed on
compacted chromosomes at a magnification
of about 1000 at metaphase.

• Preparation of a visual karyotype is done by arresting dividing cells
at metaphase stage with a microtubule polymerization inhibitor
such as colchicine; the cells, then, are spread on a glass slide and
stained with Giemsa stain (G-banding). Chromosomes are studied
by making a photograph or digital imaging and subsequent
assembling of chromosomes. Human chromos-omes are
categorized based on position of centromere; in metacentric
chromosomes, centromere is located in the middle (chromosomes
1, 3, 16, 19 and 20), chromosomes 13, 14, 15, 21, 22 and Y are
acrocentric (the centromere near one end),
• and other chromosomes are sub-metacentric. Chromosome arms
are defined by region number (from centromere), band, sub-band
and sub-sub-band numbers, e.g. 12q13.12 refers to chromosome
12, long arm, region 1, band 3, sub-band 1, sub-sub-band 2 (read
chromosome 12, q, 1, 3, point, 1, 2). High resolution banding needs
fixation before the chromosomes are fully compacted. The
convenient methods of chromosome banding are G-(Giemsa), R-
(reverse), C-(centromere) and Q-(quinacrine) banding.

• Fluorescence in situ hybridization (FISH): FISH is
applied to provide specific localization of genes
on chromosomes. Rapid diagnosis of trisomies
and microdeletions is acquired using specific
probes. Usually a denatured probe is added to a
metaphase chromosome spread and incubated
overnight to allow sequence-specific
hybridization. After washing off the unbound
probe, the bound probe is visualized by its
fluorescence under UV light; thus, the site of the
gene of interest is observed as in situ . This
technique is used to check the cause of trisomies,
microdeletion syndromes, etc.

• Comparative genomic hybridization (CGH): CGH, a special
FISH technique (dual probes), is applied for detecting all
genomic imbalances. The basics of technique is comparison
of total genomic DNA of the given sample DNA (e.g. tumor
DNA) with total genomic DNA of normal cells.
• Typically, an identical amount of both tumor and normal
DNAs is labeled with two different fluorescent dyes; the
mixture is added and hybridized to a normal lymphocyte
metaphase slide. A fluorescent microscope equipped with a
CCD camera and an image analysis system are used for
evaluation. Technical details have been described in
numerous CGH publications. Copy number of genetic
material (gains and losses) is calculated by evaluation
software. CGH is used to determine copy number
alterations of genome in cancer and those cells whose
karyotype is hard or impossible to prepare or analyze. In
array-CGH, metaphase slide is replaced by specific DNA
sequences, spotted in arrays on glass slides; so its
resolution is increased.

• Molecular Diagnostics
• In addition to genetic causes of disorders, predisposition to
a disease or treatment options could be revealed by
determining DNA variations. Molecular diagnostics provide
a way for assessment of the genetic makeup of human; it
combines laboratory medicine with molecular genetics to
develop DNA/RNA-based analytical methods for monitoring
human pathologies.
• A wide range of methods has been used for mutation
detection. Molecular methods for identification of the
disease-causing mutations could be classified as methods
for known and methods for unknown mutations.
• Several criteria, however, have to be met for choosing a
suitable method; for example the following points should
be considered: type of nucleic acid (DNA or RNA), kind of
specimen (e.g., blood, tissues, etc.), the number of
mutations, and reliability of the method.

• A) Known Mutations
• Many different approaches have been used for
identifying known mutations. Usually starting
with the polymerase chain reaction (PCR).
• DNA microarray: DNA “chips” or microarrays
have been used as a possible testing for multiple
mutations. In this technology, single DNA strands
including sequences of different targets are fixed
to a solid support in an array format. On the
other hand, the sample DNA or cDNA labeled
with fluorescent dyes is hybridized to the chip.
Then using a laser system, the presence of
fluorescence is checked; the sequences and their
quantities in the sample are determined.

• DNA Sequencing: As a powerful technique in molecular genetics,
DNA sequencing provides analysis of genes at the nucleotide level.
The main aim of DNA sequencing is to determine the sequence of
small regions of interest (∼1 kilobase) using a PCR product as a
template. Dideoxynucleotide sequencing or Sanger sequencing
represents the most widely used technique for sequencing DNA. In
this method,
• 1.double stranded DNA is denatured into single stranded DNA with
NaOH. A Sanger reaction consists of a single strand DNA, primer, a
mixture of a particular ddNTP with normal dNTPs (e.g. ddATP with
dATP, dCTP, dGTP, and dTTP). A fluorescent dye molecule is
covalently attached to the dideoxynucleotide. ddNTPs cannot form
a phosphodiester bond with the next deoxynucleotide so that they
terminate DNA chain elongation.
• 2.This step is done in four separate reactions using a different
ddNTP for each reaction . DNA sequencing could be used to check
all small known and unknown DNA variations.

• Multiplex ligation-dependent probe
amplification (MLPA): MLPA is commonly applied to screen
deletions and duplications of up to 50 different genomic
DNA or RNA sequences. Altogether gene deletions and
duplications account up to 10%, and in many disorders up
to 30% of disease-causing mutations. In this technique,
briefly,
• 1.the probe set is hybridized to genomic DNA in solution.
Each probe consists of two halves; one half is composed of
a target specific sequence and a universal primer sequence,
and other half has other more sequences, a variable length
random fragment to provide the size differences for
electrophoretic resolution.
• 2.A pair of probes is hybridized on the target region
adjacently so that they can then be joined by use of a
ligase; the contiguous probe can be amplified by PCR. After
PCR amplification, the copy number of target sequence i.e.
deletion or duplication of target sequence can be
determined and quantified using the relative peak heights.

• B) Unknown Mutations
• Single Strand Conformational Polymorphism (SSCP): SSCP is one of
the simplest screening techniques for detecting unknown mutations
(microlesions) such as unknown single-base substitutions, small
deletions, small insertions, or microinversions.
• A DNA variation causes alterations in the conformation of
denatured DNA fragments during migration within gel
electrophoresis.
• The logic is comparison of the altered migration of denatured wild-
type and mutant fragments during gel electrophoresis.
• In this technique, briefly, 1.DNA fragments are denatured, and
renatured under special conditions preventing the formation of
double-stranded DNA and allowing conformational structures to
form in single-stranded fragments .
• 2. The conformation is unique and resulted from the primary
nucleotide sequence. Mobility of these fragments is differed
through nondenaturing polyacrylamide gels; detection of variations
is based on these conformational structures.

• Denaturing Gradient Gel Electrophoresis
(DGGE): DGGE has been used for screening of
unknown point mutations. It is based on differences in
the melting behavior of small DNA fragments (200-700
bp); even a single base substitution can cause such a
difference. In this technique, 1. DNA is extracted
• 2. dna subjected to denaturing gradient gel
electrophoresis.
• 3. As the denaturing condition increases, the fragment
completely melts to single strands.
• 4. Detection of mutated fragments would be possible
by comparing the melting behavior of DNA fragments
on denaturing gradient gels.
• 5. Approximately less than 100% of point mutations
can be detected using DGGE. Maximum of a nearly
1000 bp fragment can be investigated by this
technique.

• Heteroduplex analysis: A mixture of wild-type
and mutant DNA molecules is denatured and
renatured to produce heteroduplices.
Homoduplices and heteroduplices show
different electrophoretic mobilities through
nondenaturing polyacrylamide gels. In this
technique, fragment size ranges between 200
and 600 bp. Nearly 80% of point mutations
have been estimated to be detected by
heteroduplex analysis.

• Restriction fragment length polymorphism
(RFLP): Point mutations can change restriction
sites in DNA causing alteration in cleavage by
restriction endonucleases which produce
fragments with various sizes. RFLP is used to
detect mutations occurring in restriction sites .

Dna mutation

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