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    Genetics

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    Sri Devy
    This document discusses genetic testing, including definitions, types of tests, and their uses. It provides information on: 1) Genetic testing involves analyzing DNA, RNA, chromosomes, or proteins to detect genotypes, mutations, or karyotypes associated with disease. It is used for clinical diagnosis, predictive testing, carrier screening, and research. 2) The main types of genetic tests are those for constitutional mutations present in all cells, and acquired mutations only in certain cells. Tests include molecular analysis of DNA, cytogenetic analysis of chromosomes, and biochemical analysis of gene products. 3) Genetic tests can diagnose conditions, determine cancer treatment options, identify carriers, and allow for prenatal or preimplant

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    © All Rights Reserved
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    Genetics

    Uploaded by

    Sri Devy
    377 views56 pages
    This document discusses genetic testing, including definitions, types of tests, and their uses. It provides information on: 1) Genetic testing involves analyzing DNA, RNA, chromosomes, or proteins to detect genotypes, mutations, or karyotypes associated with disease. It is used for clinical diagnosis, predictive testing, carrier screening, and research. 2) The main types of genetic tests are those for constitutional mutations present in all cells, and acquired mutations only in certain cells. Tests include molecular analysis of DNA, cytogenetic analysis of chromosomes, and biochemical analysis of gene products. 3) Genetic tests can diagnose conditions, determine cancer treatment options, identify carriers, and allow for prenatal or preimplant

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    Diagnostic tests in genetics.

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    genetics

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    This document discusses genetic testing, including definitions, types of tests, and their uses. It provides information on: 1) Genetic testing involves analyzing DNA, RNA, chromosomes, or proteins to detect genotypes, mutations, or karyotypes associated with disease. It is used for clinical diagnosis, predictive testing, carrier screening, and research. 2) The main types of genetic tests are those for constitutional mutations present in all cells, and acquired mutations only in certain cells. Tests include molecular analysis of DNA, cytogenetic analysis of chromosomes, and biochemical analysis of gene products. 3) Genetic tests can diagnose conditions, determine cancer treatment options, identify carriers, and allow for prenatal or preimplant

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    377 views56 pages

    Genetics

    Uploaded by

    Sri Devy
    This document discusses genetic testing, including definitions, types of tests, and their uses. It provides information on: 1) Genetic testing involves analyzing DNA, RNA, chromosomes, or proteins to detect genotypes, mutations, or karyotypes associated with disease. It is used for clinical diagnosis, predictive testing, carrier screening, and research. 2) The main types of genetic tests are those for constitutional mutations present in all cells, and acquired mutations only in certain cells. Tests include molecular analysis of DNA, cytogenetic analysis of chromosomes, and biochemical analysis of gene products. 3) Genetic tests can diagnose conditions, determine cancer treatment options, identify carriers, and allow for prenatal or preimplant

    Copyright:

    © All Rights Reserved
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    Download as pptx, pdf, or txt
    of 56

    Genetic testing basis of

    genetic diagnosis, Pre


    symptomatic and
    predisposition testing

    Definition of Genetic
    Testing:
    The analysis of human DNA
    in any of its forms or related
    products (chromosomes,
    RNA, proteins)

    Genetic Testing
    involves the direct examination
    of the DNA molecule itself. A
    scientist scans a patient's DNA
    sample for mutated sequences.
    Genetic testing is done for a
    particular condition where an
    individual is suspected of being at
    increased risk due to their family or

    Genetic Testing
    Getting an informed consent
    Genetic tests are performed on the
    sample of blood, skin , hair, amniotic
    fluid, chorionic villus sampling, or
    other tissue.
    Should be accompanied by genetic
    counselling.

    More definitions

    Genotype vs. Phenotype


    The genetic make-up, as distinguished
    from the physical appearance

    Mutation
    A genetic change, usually one that is
    associated with a disease

    Karyotype
    A visual presentation of
    chromosomes

    Indications
    Maternal risk factors
    - Advanced maternal age,>35 yrs
    - F/H of previous baby with NTD/
    chromosomal anomaly.
    - Maternal diabetes, epilepsy, alcoholism
    - H/o recurrent miscarriage
    - Abnormal maternal serum triple marker
    screening test / abnormal serum AFP
    - Exposure to medications during pregnancy

    -Oligohydramnios or polyhydramnios
    -Rubella/ cytomegalovirus infection

    Pediatric risk factors


    -positive neonatal screening test
    -Known chromosomal abnormality
    -Delay in growth and development
    -Mental retardation

    When testing the DNA, it is extracted from the tissue, cut into pieces
    by chemical scissors and then the pieces are separated on a gel.
    The piece of DNA of interest that contains a particular gene can be
    selected from the20,000 or so genes in an individuals DNA using a

    Uses of Genetic Testing

    Uses of Genetic Testing:


    To detect disease-related genotypes, mutations,
    phenotypes, or karyotypes for clinical purposes
    Helps people to make informed decisions about
    managing their health care.
    Help couples to decide whether to continue or
    terminate the pregnancy.
    Neonatal screening helps to identify genetic
    disorders so that early treatment can be started to
    prevent the harmful irreversible effects.
    Early detection of cancer genes enable the carriers
    to take necessary preventive measures and regular

    Parental testing is the use of genetic


    fingerprinting to determine whether two
    individuals have a biological parentchild
    relationship

    Diagnosis- A direct gene test can be used to


    diagnose a genetic condition. This can be very
    useful when the clinical picture is not clear.

    The two fragments of DNA represent the


    faulty gene copy and the working gene
    copy. The bands are heavier from
    persons A and C as there are two copies
    of the same gene at each band. Person A
    has two copies of the faulty gene; person
    B has one faulty copy and one working
    copy (ie. a carrier of the faulty gene) and
    person C has two copies of the working

    Types of genetic
    tests

    Genetic Carrier Screening


    The term genetic carrier screening
    is used to describe direct gene
    testing applied to a whole population
    or to a defined group.
    For example, genetic carrier
    screening may be available for
    people in the population who have no
    personal or family history of a
    condition but who have a greater
    than average chance of carrying a

    Newborn Screening
    The blood sample is taken by a heelprick before the baby leaves hospital,
    or for home births, on about day 4,
    and is sent to a special laboratory.

    Presymptomatic Genetic
    Testing

    The detection of a faulty gene in a person


    with a
    family history of a particular
    condition, but who currently has no
    symptoms of that condition, means that that
    person will certainly develop the condition in
    later life.

    Predictive Genetic
    Testing
    Sometimes the detection of the
    faulty gene provides the person
    with an increased risk estimate,
    rather than certainty, that they will
    develop a particular condition later
    in life.
    Predictive testing for some families
    is available for inherited conditions
    such as an inherited predisposition
    to haemochromatosis or breast

    Prenatal testing This is done to detect any genetic abnormality in


    the fetus. This type of tests is suggested to
    couples who are known carriers or have a
    previous baby with genetic or chromosomal
    disorder.
    Forensic testing
    This uses DNA finger printing technique to
    identify criminals or catastrophe victims, or
    establish biological relationships in case of a
    disputed parentage.
    Research testing
    This is done to find unknown genes, to learn how
    genes work and to advance our understanding of

    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
    occurred later in life

    Genetic Tests for Constitutional


    Mutations

    Molecular Tests
    Cytogenetic Tests
    Biochemical Tests

    Molecular Test: Example


    Analysis of DNA
    sequence in patient
    with a rare 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

    Molecular Test: Muscular


    Dystrophy
    Obtain blood sample from child
    Read the DNA sequence of the DMD
    gene
    Identify the mutation that caused the
    disease

    How is this information


    useful?
    To test Mom Is she an unaffected
    carrier of the mutation? Is she at risk
    to have more children with this
    disease?
    to test siblings of affected child
    to offer prenatal diagnosis in Moms
    next pregnancy OR
    to offer pre-implantation genetic
    diagnosis
    to provide information about
    prognosis

    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

    Cytogenetic Test: Child with MCA


    and autism
    Obtain a
    blood
    sample from
    baby
    Look at
    chromosom
    es

    How is this information


    useful?
    To determine exactly which genes
    are involved
    to test parents and siblings of
    affected child to see if they carry the
    abnormality
    To offer prenatal diagnosis in next
    pregnancy OR
    to offer pre-implantation genetic
    diagnosis
    to provide information about
    prognosis

    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

    Biochemical Test: PKU

    Phenylketonuria
    Inherited metabolic disorder
    If untreated, leads to mental retardation, seizures
    Affects 1 in 20,000 newborns

    Missing enzyme:
    Phenylalanine Hydroxylase
    Measure amount of
    Phenylalanine in babys
    blood

    How is this information


    useful?
    To diagnose the baby in
    time, to treat and avoid all
    clinical consequences of the
    disease
    Treatment: Restrict
    phenylalanine in the diet

    to test siblings of affected


    child, to see if they are
    carriers for the disease (1 in
    70 in the general population
    are carriers)

    Genetic Tests for Acquired Mutations

    Molecular Tests
    Cytogenetic Tests
    Tests for changes that affect only certain
    cells
    or cell types in the body, and that occurred
    later in life

    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

    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

    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

    Cytogenetic Test for Acquired


    Disease
    FISH (Fluorescent In Situ Hybridization)
    for HER-2/neu is a gene-based test that
    allows one to count the number of HER2 genes in a cell.

    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 patients unlikely to
    respond

    Interpreting results of genetic tests


    -A positive test may confirm a diagnosis or
    suggest a need for further testing. It may have
    implications for certain blood relatives of the person
    undergoing testing and may require their screening
    for the same genetic condition.
    -A negative result can indicate that a person is
    not affected by a particular disorder, is not a carrier
    of the abnormal gene or does not have the
    increased risk of developing the disease.

    Predictive genetic testing


    Conventional medical diagnostic test
    Individual patient
    Current status

    Predictive genetic test


    Direct implications for family members
    Future condition (that may or may not develop)
    ??whether ??when ??how severe ?? Benefits
    of intervention

    Usually not determinative

    Predictive genetic testing for


    presymptomatic /predisposed individuals
    MEN2
    Full penetrance, thyroid Ca

    Colorectal cancer
    Colonoscopy surveillance

    Breast cancer
    ?? Penetrance
    ?? Treatment options

    Hemochromatosis
    Low penetrance
    Modifiers: sex, diet, alcohol
    Phenotypic screening

    Hereditary Hemochromatosis
    Common 2-5/1000
    iron overload
    Clinically serious
    liver cirrhosis and
    1o hepatic carcinoma
    diabetes mellitus
    cardiomyopathy
    endocrinopathy
    arthropathy

    Treatable: phlebotomy

    Hereditary
    Hemochromatosis-2
    Modifiers of Phenotype
    Sex (protective effect of menses,
    pregnancy)
    Dietary iron vs blood loss
    Alcohol intake
    Mendelian disease that
    behaves like a common complex disease

    Hereditary
    Hemochromatosis-3
    Why not screen everyone ?
    Gene test available: HFE on
    chromosome 6
    C282Y high penetrance
    H63D
    low penetrance, common

    Phenotypic screening available


    Iron, TIBC ,ferritin

    What does a positive test mean ?


    Family screening vs Population
    screening

    Utility of testing

    Evans et al. BMJ 322:1052-56


    (2001)

    Presymptomatic Diagnosis
    Definition (P.Harper, 1997) = situations
    where an abnormal result indicates that the
    disease will almost develop at some point in
    life.
    New Genetic Medicine:
    - High risk asymptomatic persons (~ 50%)
    for genetic disease
    - Late-onset disorders
    - Monogenic mendelian disorders

    Presymptomatic Diagnosis
    Knowledge of genetic status of
    asymptomatic individuals at risk for
    developing an identified genetic disorder
    Concerned persons :
    - at risk
    - adults
    - asymptomatic (absent features)
    - Voluntary consent

    Presymptomatic Diagnosis
    Key notion of medical benefit
    2 different situations :
    - Possible preventive/curative treatment
    (ex: cancer predisposition)
    No preventive/curative treatment available
    (ex: neurodegenerative disorders)
    Model = Huntington disease

    Presymptomatic Diagnosis
    France (Dcret 2000-570) :
    conditions of prescription of genetic
    testing
    Multidisciplinary teams (Ministry of
    Health)
    HD: geneticist, neurologist,
    psychologist
    Care and testing (4-6 months)

    Presymptomatic Diagnosis
    Justifications
    To relieve uncertainly about genetic
    status 54 %
    To plan a family
    14 %
    To plan for the future
    13 %
    To inform the children

    Presymptomatic Diagnosis
    Remarkable events

    Pregnancy
    20 %
    (50 % PND; 50 % MA)
    Serious adverse events:
    - Psychological distress and
    depression 9 %
    - Psychiatric hospitalization

    Presymptomatic Diagnosis
    Conclusions
    New concept
    Molecular genetic advances :
    2 care levels:
    - Severe diseases :
    SCA, hereditary dementia/Alzheimer
    - Mild diseases :
    CMT, FSH myotonic dystrophy

    Genetic Testing in Children

    Information, free choice, consent : not possible in


    children, choice of the parents
    Possible in symptomatic children (CF, DMD ..)
    Possible: medical benefit in asymptomatic child:
    - curative/preventive treatment: cancer
    predisposition syndromes (APC, Gorlin )
    - screening/follow-up (Steinert, glaucoma )
    - professional/social orientation ( CMT )

    Genetic Testing in Children


    Genetic tests forbidden in asymptomatic
    child :
    Severe late-onset genetic disorders
    - Hereditary cancer predisposition (BRCA1,
    BRCA2, HNPCC )
    - Neurodegerative late-onset diseases (HD,
    SCA, CADASIL )
    Recessive heterozygous status
    Multigenic/polyfactorial heredity

    Genetic Testing in Children


    Personal benefit for the child
    Preventive/curative treatment for the
    family
    Deprivation of the right of notknowing
    Breakdown in the child-parents
    relationship
    Disease anticipation

    Approach to genetic testing in


    children
    According to the American Society of Human
    Genetics, the following categories of genetic
    testing is being followed.
    Category I- Disorders requiring immediate
    treatment/ prevention/ surveillance
    Category II- Testing Asymptomatic carrier to
    define reproductive risks
    Category III- Testing healthy young person with
    predisposition to develop disease
    Category IV- Testing healthy young person who
    will develop disease

    Category I- Disorders requiring


    immediate treatment/ prevention/
    surveillance
    Eg. PKU,MEN,FAP,XSCID,
    hyperlipidemias etc.,
    Category II- Testing Asymptomatic
    carrier to define reproductive risks
    Eg. Xlinked disorders ( hemophilia,
    muscular dystrophy,XSCID),
    autosomal disorders (cystsics fibrosis,
    sickle cell disease, Tay-sachs disease)

    Category III- Testing healthy young


    person with predisposition to
    develop disease
    Eg. Familial breast
    cancer(BRCA1,BRCA2) and HNPCC.
    Category IV- Testing healthy young
    person who will develop disease
    Eg. Huntingtons disease, some forms
    of Parkinsons disease and PKD

    Summary
    Constitutional genetic tests impact
    patients with inherited disorders and their
    families, by providing information about
    diagnosis, prognosis, treatment, and
    informing reproductive decisions
    Genetic tests for acquired diseases impact
    patients with diseases like cancer, provide
    information about diagnosis and
    prognosis, and inform treatment decisions
    Genetics and genetic testing impacts
    many phases of our lives, and will do so
    even more in the future

    Thanks

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