genetic testing in individuals and in population
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GENETIC TESTING IN
INDIVIDUALS AND IN
POPULATION
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INTRODUCTION
Genetic testing is a type of medical test that identifies
changes in chromosomes, genes, or proteins.
Most of the time, testing is used to find changes that are
associated with inherited disorders.
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WHY GENETIC TESTING?
The results of genetic testing may help
Diagnose a disease.
Find genetic difference that may increasethe individuals risk of getting a disease.
Find genetic diseases that could be
passed onto the individuals children.Guide the health care provider to choose
the best treatment for diagnoses.
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SAMPLES FOR GENETIC TESTING
Genetic test are performed on a sample of
Blood
Cells swabbed from the mouth
SalivaSkin
Hair
TumorsAmniotic fluid/ chorionic villus samples.
Urine
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Genetic diagnosis can be made in two essentially different
ways
Direct testing:
a sample from the consultand is tested to see whether he has acertain genotype or not, typically a pathogenic mutation in a certaingene. IT IS THE TEST OF AN INDIVIDUAL.
Gene tracking:
linked markers are used in family studies to discover whether or notthe consultand inherited the high risk chromosome from aheterozygous parent. IT IS TEST OF THE FAMILY.
gives information about the segregation of the chromosomalsegment in the family.
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Two Main Types of Genetic Tests
Constitutional
Tests for mutations that affect ALL CELLS in
the body, and have been there since
conception
Acquired
Tests for changes that affect only certain cells
or cell types in the body, and that occurredlater in life
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Genetic Tests forConstitutional Mutations
Molecular Tests
Cytogenetic Tests
Biochemical Tests
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Molecular Test: Example
Analysis of DNA sequence in patient with arare inherited disease Muscular Dystrophy
Gene: DMD Clinical Picture
1 in 3500 male births
progressive muscle weakness starting in early childhood
wheelchair by age 12 death in 20s
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Molecular Test: Muscular Dystrophy
Obtain blood sample from child
Read the DNA sequence of the DMD gene
Identify the mutation that caused thedisease
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How is this information useful?
Can test Mom Is she an unaffected carrier ofthe mutation? Is she at risk to have morechildren with this disease?
Can test siblings of affected child Can offer prenatal diagnosis in Moms next
pregnancy OR
Can offer pre-implantation genetic diagnosis
Can provide information about prognosis
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Cytogenetic Test: Example
Karyotype to examine the chromosomal
complement of an individual including
number, form, and size of the
chromosomes.
Frequently used for children who present
with multiple anomalies, developmental
delay, autism.
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Cytogenetic Test: Child with MCA
and autism
Obtain a blood
sample from baby
Look at
chromosomes
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CGH
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ARRAY CGH
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How is this information useful?
Can determine exactly which genes areinvolved
Can test parents and siblings of affected child
to see if they carry the abnormality Can offer prenatal diagnosis in next pregnancy
OR
Can offer pre-implantation genetic diagnosis
Can provide information about prognosis
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Biochemical Test
Analyzes the quantity of a downstream
product of a gene (e.g. not looking directly
at the gene, or the chromosome).
Example: Newborn Screening
Mandated in all 50 states
Twenty primary targets that all states do
Over 4 million newborns tested each year
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Biochemical Test: PKU
Phenylketonuria Inherited metabolic
disorder If untreated, leads tomental retardation
Affects 1 in 20,000newborns
Missing enzyme:phenylalaninehydroxylase.
Measures the amount ofphenylalanine in blood.
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How is this information useful?
Can diagnose the baby in time to treat and
avoid all clinical consequences of the
disease
Treatment: Restrict phenylalanine in the diet
Can test siblings of affected child to see if
they are carriers for the disease (1 in 70 in
the general population are carriers)
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Genetic Tests forAcquired Mutations
Molecular Tests
Cytogenetic Tests
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Molecular Test for Acquired Disease
KRAS gene test on tumor tissue from
patients with colorectal cancer
Obtain tumor from patient
Extract DNA; treat with enzyme that allows
visualization of the mutation
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How is this information useful?
Patients whos colon tumors do not have a
KRAS mutation are much more likely to
respond to Cetuximab therapy
Identifies patients most likely to benefit
from specific therapies
Allows choice of alternative therapies (and
saves time and money) for patients
unlikely to respond
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Cytogenetic Test for Acquired
Disease: Example
Her-2/neu gene amplification in Breast
Cancer
Occurs early in oncogenesis
Seen in up to 1/3 of breast cancers
Associated with poor prognosis
Responds to Herceptin (trastuzumab)
treatment Does not respond to Tamoxifen treatment
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How is this information useful?
Assists in selection of patients for
chemotherapy, and which therapy to use
Predicts response to adjuvant therapy
Increases survival
Allows choice of alternative therapies (and
saves time and money) for patientsunlikely to respond.
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TYPES OF GENETIC TESTING
Newborn screening
Carrier testing
Diagnostic testing
Preimplantation testing
Predictive testing/ presymptomatic testing
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NEWBORN SCREENING
Used just after birth to identify genetic disorders that canbe treated early in life.
Look forabnormal arrangements of chemical bases in
the gene itself while other test detect inborn errors ofmetabolism.
Millions are infants are tested each year in united states
forphenylketonuria and congenital hypothyroidism.
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CARRIER TESTING
Used to identify people who carry one copy of gene
mutation that, when present in two copies causes a
genetic disorder
Offered to individuals who have a family history of a
genetic disorder and to people in certain ethnic groups
with an increased risk of specific genetic conditions.
If both parents are tested, the test can provide
information about a couples risk of having a child with
genetic condition.
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DIAGNOSTIC TESTING
Used to identify / rule out a specific
genetic chromosomal condition
Genetic testing is used to confirm a
diagnosis when a particular condition is
suspected based on physical signs and
symptoms.
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PRENATAL TESTING
To detect changes in a fetus genes/
chromosomes before birth.
Offered during pregnancy if there is an
increased risk that the baby will have a
genetic / chromosomal disorder.
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PREIMPLANTATION TESTING
Used to detect changes in the embryos
that were created using assisted IVF.
Small number of cells are taken from the
embryos and tested for certain genetic
changes
Embryos without these changes are
implanted in the uterus to initiate a
pregnancy.
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PREDICTIVE/PRESYMPTOMATIC
TESTING
Used to detect gene mutations associated with
disorders that appear often later in life.
Predictive testing- identify mutations that
increase a persons risks of developing diseaseswith genetic basis, such as certain type of
cancer.
Presymptomatic testing- determine whether a
person will develop a genetic disorder, before
any signs or symptoms appear.
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MUTATION SCANNING METHODS
Detection of known genetic mutations Allele Specific Oligonucleotide (ASO)
Amplification Refractory Mutation System ( ARMS)
Oligonucleotide Ligation Assay (OLA)
Detection of unknown genetic mutations Denaturing high performance liquid chromatography (DHPLC)
Single strand conformation an polymorphism(SSCP)
Denaturing gradient gel electrophoresis (DGGE )
DNA microarray
Protein truncation test (PTT)
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OLIGONUCLEOTIDE LIGATION ASSAY
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ALLELE SPECIFIC OLIGONUCLEOTIDE
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AMPLIFICATION REFACTORY MUTATION SYSTEM
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PROTEIN TRUNCATION TEST
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DHPLC
Most sensitive method that provides a high degree of automation
and throughput.
Detects successfully single nucleotide substitutions, small deletions,
insertions within 2.5 minutes in unpurified amplicons as large as 1.5
kb
Detects mutation on the basis of mismatches between amplified
chromosomal fragments that results in the formation of
heteroduplex.
stationary phase-polystyrene divinyl benzene
Ion pairing reagent- triethylammonium acetate Mobile phase-acetonitrle
Sensitivity doesn't drop over a size of150-700 bp.
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DGGE
DNA MICROARRAY
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DNA MICROARRAY
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GENE TRACKING
Steps involved
Distinguish the two chromosomes in
relevant parents i.e. to find closely linked
marker for which they are heterozygous.
Determine phase
Work out which chromosome the
consultand received.
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RFLP
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Thank you
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