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    Diagnostic Odysseys

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    Dr. Dusica Babovic-Vuksanovic is Geneticist and Chair of the Department of Medical Genetics and the Director of Neurofibromatosis Clinic. She is a Professor of Medical Genetics and Pediatrics at the Mayo Clinic.

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    Diagnostic Odysseys

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    Dr. Dusica Babovic-Vuksanovic is Geneticist and Chair of the Department of Medical Genetics and the Director of Neurofibromatosis Clinic. She is a Professor of Medical Genetics and Pediatrics at the Mayo Clinic.

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    Dr. Dusica Babovic-Vuksanovic is Geneticist and Chair of the Department of Medical Genetics and the Director of Neurofibromatosis Clinic. She is a Professor of Medical Genetics and Pediatrics at the Mayo Clinic.

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    149 views55 pages

    Diagnostic Odysseys

    Uploaded by

    National Press Foundation
    Dr. Dusica Babovic-Vuksanovic is Geneticist and Chair of the Department of Medical Genetics and the Director of Neurofibromatosis Clinic. She is a Professor of Medical Genetics and Pediatrics at the Mayo Clinic.

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    Diagnostic Odysseys

    Dusica Babovic-Vuksanovic, MD
    Professor of Genetics and Pediatrics
    Chair, Department of Medical Genetics
    Center for Individualized Medicine, Mayo Clinic

    GENETICSvery
    simple!
    Mendelian disorders
    Autosomal dominant
    Autosomal recessive
    X-linked

    Autosomal dominant
    inheritance
    Neurofibromatosis
    Tuberous sclerosis
    I

    II

    III

    Marfan syndrome
    Ehlers-Danlos
    syndrome
    Familial cancer
    syndromes
    Achondoplasia

    Autosomal recessive
    inheritance

    Cystic fibrosis
    Metabolic
    disorders
    Syndromes25%

    Carrier

    25%

    25%

    25%

    Normal
    Affected

    X-linked
    inheritance
    Fragile X
    Duchenne muscular dystrophy
    Hemophilia A

    Affected male
    Normal male
    Normal female
    Carrier female

    Risk for disease


    CAD
    70s

    Colon Ca
    80s

    Lung Ca
    75

    55 y
    Cleft
    Palate
    MR

    45 y
    BRCA

    32 y

    30 y

    48 y
    MI

    20 y

    Dementia

    MVA
    15 y

    18 y

    Dementia

    Genetics of human disease


    Is it so simple?
    Mitochondrial disorders
    Maternally inherited
    mDNA

    Epigenetics mechanisms
    ANGELMAN SYNDROME PRADER WILLI SYNDROME
    Paternal
    Maternal
    deletion/maternal UPD
    deletion/paternal UPD
    Hypotonia
    Stiff ataxic gait
    Developmental delay
    Severe MR
    Obesity
    Absent speech
    Hypogonadism
    Almost never obese
    OCD

    Genetic
    heterogeneity

    Several genetic loci for


    the
    same phenotype
    Neuropsychiatric
    disorders
    Autism
    Schizophrenia
    Hearing loss

    Non-syndromic
    >400 syndromes
    Cell, Volume 141, Issue 2, 210-217, 16 April 2010

    Allelic heterogeneity:
    same gene-different
    phenotypes
    FGFR3
    Achondroplasia
    Crouzon syndrome/AN
    Thanatophoric
    dysplasia

    LAMIN A
    Progeria
    ED Muscular
    dystrophy
    Cardiomyopathy
    Lipodystrophy

    Variable
    penetrance
    Incomplete penetrance
    Deletion/duplication 22q
    Age dependent penetrance
    Alzheimer disease
    Gender predisposition
    X-linked disorders
    Hip dysplasia

    Anticipation
    Trinucleotide repeat disorders
    Huntington disease
    Spinocerebellar ataxia
    Myotonic Dystrophy
    Fragile X syndrome

    New Frontiers
    Environment, including
    microbiome

    If the child looks like the father, its genetic


    f the child looks like the neighbor, its environmenta

    No rules? COMPLICATED
    Non-Mendelian (common) disorders
    Multifactorial disorders
    Genetics/environment complex
    interactions
    Cleft lip/palate
    Cancers
    Diabetes
    Hypertension
    Aging..

    DNA
    (A, G, T, or C)
    is 6 billion bits in
    every cell, with a
    total length of
    about 6 feet of
    DNA in every cell

    From Nature, Feb 2001

    Information
    content of human

    Human genome

    ~ 25,000 genes
    Over 3,000 monogenic disorders
    Human genome variations (Craig Venter)
    3,213,401SNPs
    53,823 block substitutions (2206 bp)
    559,473 homozygous indels (182,711 bp)
    62 CNVs
    292,102 heterozygous insertion/deletion events
    (indels)(1571 bp)
    90 inversions
    Levy et al., PLoS Biol. 2007 October; 5(10): e254

    Personalized medicine: Era of


    genomic sequencing
    Risk for disease
    Predict response to
    drugs
    Pre-symptomatic
    diagnosis for
    preventable and
    treatable disease

    Translation to clinical
    medicine
    Incidental findings
    Ethical concerns
    Emotional distress
    Cost of medical care

    Gene screening may refine


    prediction of heart attack risk,
    researchers say
    Dec. 3, 2010 | This Week at Mayo Clinic | Volume 2, Number 1

    Testing for 11 specific genetic variations in hundreds of people


    with no history of heart disease provided information that led to
    revision of their estimated heart attack risk, say Mayo Clinic
    researchers.
    Early findings suggest benefit may be most valuable in people thought to
    be at intermediate risk using the current model
    Dr. Kullo adds, however, that these findings need to be replicated and validated
    in prospective studies before they are used in patient care.

    What is a Diagnostic
    Odyssey?
    A protracted and arduous journey for
    patients and families to find answers about
    a rare medical condition they suffer from
    A long sequence of medical evaluations
    and referrals until patients have an
    eventual diagnosis
    Rare diseases affect about 25 million
    people in the US
    Cumulatively, rare diseases are not rare

    Diagnostic Odyssey in the


    Era of Precision Medicine
    25% of patients on a diagnostic odyssey
    identified a gap of 5 to 30 years between
    getting their first symptoms and receiving
    diagnosis
    With advancements in genome sequencing
    more patients are finding answers to their
    diagnostic dilemmas
    Some
    are
    treatments

    even

    finding

    lifesaving

    Genetic testing
    Cytogenetic methods (karyotype, FISH etc)
    Chromosome analysis
    Chromosome microarray
    Targeted microdeletion/duplication testing
    Molecular methods (sequencing, UPD, methylation
    assay etc)
    Single gene analysis
    Gene panels
    Exome analysis
    Genome analysis

    21

    From Gregory, Nature Reviews Genetics 6, 699-70

    Genome sequencing

    23

    6 billion
    bases!
    lgvrdlmnqvtthequickababcmfxlqbrownfoxjulrcsmped
    overthelazyyyzpolfdogjjirttiythedoglayhhbeldquetly
    dreaminghwwiqldnsofdinnerplwosiucnd

    25

    Whole Exome Sequencing


    (WES)
    Analysis of all exons
    180,000 exons arranged in ~22,000 genes
    Portion of the human genome that contains proteincoding
    sequences
    2-3% of human genome

    26

    Whole Exome Sequencing


    (WES)
    Genes related to clinical phenotype
    Medically actionable diagnosis (ACMGG guidelines)
    Carrier status for AR conditions (CF, Tay-Sachs, Sickle
    Cell, Familial Dysautonomia, Canavan disease, G6PD
    deficiency)
    Pharmacogenetic information (CYP2C9 and
    CYP2C19), warfarin and Plavix metabolism
    Not included adult onset neurodegenerative
    disorders
    Optional expended report includes deleterious
    mutations and unclassified variants in genes
    unrelated to disease phenotype and deleterious
    mutations in genes with no currently known function
    27

    Whole exome sequencing


    Need to have
    parental samples
    Complex test and
    difficult interpretation
    Variants of
    unknown
    significance (VUS)
    Incidental findings

    Were not all the same


    28

    Individualized Medicine (IM)


    Clinic
    IM Clinic Workgroup established in January
    2012
    Multidisciplinary, collaborative effort
    Designed/implemented two IM Clinic service
    lines

    Sept 30th, 2012:


    Advanced Cancer
    Diagnostic Odyssey

    IM Clinic: Diagnostic Odyssey


    Undiagnosed patients with suspected
    genetic component
    Whole Exome Sequencing of patient
    genomic DNA and affected or unaffected relatives - performed to find
    genes contributing to disease
    Dx provides:
    Comfort, resolve, closure
    Information for family planning
    Possible therapy

    Diagnostic Odyssey
    IM Clinic
    eConsult

    Referral into
    IM Clinic

    Referral to
    Mayo Clinic

    Whole
    Whole Exome
    Exome Sequencing
    Sequencing
    of
    of germ-line
    germ-line

    Genomic
    Genomic counseling
    counseling
    IM
    IM Clinic
    Clinic Consultant
    Consultant meets
    meets patient
    patient

    Bioinformatics
    Bioinformatics
    analyzes,
    analyzes, generates
    generates
    report
    report
    Results
    Results presented
    presented to
    to
    Genomic
    Genomic Board
    Board
    Results
    Results and
    and possible
    possible
    treatment
    treatment options
    options
    returned
    returned to
    to patient
    patient

    What is Standard Lab


    Order?

    IM Clinic
    Genomic Odyssey Board (GOB)
    Review new cases and test results.
    Members include:

    Diagnostic Odyssey
    Case 1
    Holoprosencephaly
    Central incisor
    Facial clefting
    Diabetes insipidus
    Ectrodactyly
    Developmental delay

    ECC (TP63 gene)


    negative
    Normal chromosome
    array
    Odyssey case!

    Hartsfield syndrome

    35

    Hartsfield syndrome
    Autosomal disorder
    Only sporadic cases known
    Recurrence risk low?

    36

    Second child
    Ectrodactyly
    Holoprosencephaly
    Cleft lip and palate
    Heart defect

    Hartsfield syndrome
    No other reported familial cases
    WES: FGFR1 gene novel variant c.1880G>C
    (p.R627T)
    2 affected siblings with same mutation, parents
    negative
    Recurrence risk?

    Third child
    Ectrodactyly
    Holoprosencephaly
    Cleft palate
    Encephalocele

    3 affected siblings with same mutation, parents


    negative, Odyssey continues!
    Targeted testing of sperm: 23% of cells with the
    mutation

    Diagnostic Odyssey Case 2

    Age : 26
    Sex : Male
    Progressive muscle weakness onset age 6 or 7
    Difficulty sitting and standing up from sitting
    position and difficulty climbing stairs
    Difficulty swallowing solid foods
    Mild form of ophthalmoplegia
    Elevated CK (643)

    Previous Genetic Testing


    Prior muscle biopsies not specific
    No genetic testing (insurance problems)
    Referred for WES

    IM evaluation
    Personal history
    Pedigree analysis
    Physical examination
    Review of previous evaluations
    Differential diagnosis
    Review of literature

    44

    Results

    Progressive myopathy, suspicious family history,


    Hutterite ancestry
    Limb-girdle muscular dystrophy type 2H Sarcotubular myopathy
    Autosomal recessive disorder previously described
    in Hutterite population
    Targeted gene testing

    IM Clinic Diagnostic Odyssey


    Consecutive Cases of 18 Months in
    Operation

    MedGen
    Non
    MedGen
    Total

    All Referrals
    Declined
    Proceeded with
    WES
    WES* testing
    testing
    42
    23
    8
    50

    Total
    65

    17

    32

    82

    IM Clinic Diagnostic Odyssey


    Consecutive Cases of 18 Months in Operation
    Reason for Referral
    Age
    Neuro

    5<5
    18

    >18

    Total

    All referred 17 26

    50

    All tested with WES 10 15

    31

    All positive 1

    All referred 2

    24

    32

    All tested with WES 1

    14

    19

    All positive 0

    Non-neuro

    IM Clinic Diagnostic Odyssey


    Consecutive Cases of 18 Months in
    Operation
    Cases
    Total Complete

    50

    Positive

    15

    Negative

    35

    Success Rate

    30%

    IM Clinic Diagnostic Odyssey


    Consecutive Cases of 18 Months in Operation
    Results from Clinical Focused report
    Tota
    l

    Range per
    patient

    22

    0-3

    Medically actionable*

    0-1

    Carrier status

    0-1

    76

    0-4

    223

    0-16

    5.6

    Pathogenic/likely pathogenic
    mutations

    **PGX
    ***VUS possible related to
    phenotype

    * Medically actionable -- MUTYH (het), DSC2 Carrier - CFTR, G6PD, FANCC


    ** PGX: Pharmacogenomics
    ***Variants of unknown clinical significance

    Averag
    e

    Cost for Evaluating a Patient on


    a
    Diagnostic Odyssey
    Success
    Rate

    Cost

    Conventional Genetic
    Testing*

    15%

    ~$25,0
    00

    Whole Exome Sequencing

    30%

    $8,000

    Tests

    * Shashi V et al., Genet Med 16;176-2;2014

    IM Clinic Diagnostic Odyssey


    Party Responsible for Payment
    %

    Category
    Patients received complete or
    31 partial commercial insurance
    coverage
    27

    Medicaid

    18 CIM
    6

    International patients

    18 Other

    WES and Still No Diagnosis:


    What
    is
    Next
    Associated
    Variant Type
    Phenotype(s)

    Repetitive DNA, including


    trinucleotide repeats

    Fragile X syndrome
    Huntingtons disease

    Copy-number variants

    DiGeorge syndrome
    Charcot-Marie-Tooth disease type 1A

    Long insertion-deletion variants*

    Resistance to HIV infection

    Structural variants

    Chromosomal translocations
    associated with spontaneous
    abortions

    Aneuploidy

    Downs syndrome
    Turners syndrome

    Epigenetic alterations

    Prader-Willi syndrome, BeckwithWiedemann syndrome

    Acknowledgeme
    nts
    Center for Individualized Medicine
    Leadership
    Konstantinos N. Lazaridis, M.D.

    Department of Medical Genetics


    David R. Deyle, M.D.
    Pavel Pichurin, M.D.
    Ralitza Gavrilova, M.D.
    Geoffrey Beek, CGC
    Jennifer Kemppainen, CGC
    Marine Murphree, CGC

    Questions

    Were not in the post-genome era yet!

    Fromhttp://www.infosci.coh.org/corelab/genomics.htm

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