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TRANSCRIPT
Precision Medicine
Douglas Riegert-Johnson, MDAssistant Professor of Medicine and Medical GeneticsMayo Clinic Florida
2015 Mayo ClinicClinical ReviewsAmelia Island
Douglas Riegert- [email protected] Clinic FloridaMedical Genomics and GI
Kimberly [email protected] Clinic FloridaMedical Genomics
IntroductionIndications and Implementation
Mayo Clinic Florida Website
Hyperlinks
Conflicts of Interest and Off Label Drug Use
The presenters have no commercial interest in any of the products discussed.
No off label drug use will be discussed.
Top 3 questions
What about 23andme: direct-to-consumer saliva test? 23andme only offering ancestry testing, connecting relatives, raw data
and carrier testing for Bloom syndrome. Not allowed to offer their previous interpretive report by FDA.
What about gene therapy? Slow progress. R
ecent success with a rare form of blindness (2/6 pts with choroideremia). Approved for one rare disease (lipoprotein lipase deficiency).
Can I have my entire genome sequenced and the results given to me in accessible format? Closest easily accessible commercially available product is testing of
1,691 of 22,000 genes ($9,500 cash up front, Illumina).
3
Objectives
Introduce and define Precision Medicine
Review the current clinical indications for Precision Medicine
Cover the implementation of Precision Medicine
Big Hero Six: Precision medicine in popular culture2014 Academy Award Best Animated Movie
Hiro Hamada is a 14-year-old robotics genius living in the futuristic city of San Fransokyo.
BayMax: Personal health care companion
Character in Disney’s Big Hero 6
He is the personalized health care companion for Hiro.
Although, no genetic/genomic testing involved, epitomizes many of the perceptions of precision medicine (technology)
Baymax scans Hiro to assess his individual health care needsMovie Excerpt 2 min “Discovery”
CLIP
Precision Medicine
Douglas Riegert-Johnson, MDAssistant Professor of Medicine and Medical GeneticsMayo Clinic Florida
Mayo ClinicClinical ReviewsAmelia Island
Douglas Riegert- [email protected] Clinic FloridaMedicine and Medical Genetics
1.IntroductionWhat is it?
Introduction to Precision Medicine: Defining the terms
Precision Medicine = Individualized Medicine
Precision Medicine = Personalizing medical care with DNA testing
Precision Medicine = Personalizing medical care using DNA testing of many different genes at the same time
Precision Medicine by genomics Once technology advances other –omics to be added, like proteomics
Hold on, what happened to genetics?
Genetics = classical single gene testing
Examples: Dilated aortic root > Marfan FBN1 gene testing
Genetics has retired > Genomics is now!
1994 – BRCA1 isolatedLion King top grossing animated film
Genetic Testing Then•Expensive•Usually not covered by insurance•Weeks to arrange, months for results
Genomic Testing Now•Drastic reduction in cost•Often covered at least in part by insurance•Significant reduction in turnaround time
BRCA1
BRCA2
ATM
BARD1MSH2MSH6 MLH1
PALB2
NF1
CHEK2
CDH1TP53
RAD50
PMS2
Genetics 2 genes $4200 12 weeks
Genomics 14 genes $2000 ($100) 4 weeks
Genomics made possible by NEXT GENeration Sequencing.
Like microbots they are mindless NEXT GEN the name
for numerous disruptive technologies used for high through put low cost DNA sequencing
Ion torrent
NEXT GENeration technologies generate data, not diagnoses, treatments or cures
Precision Medicine
Douglas Riegert-Johnson, MDAssistant Professor of Medicine and Medical GeneticsMayo Clinic Florida
The testing of multiple genes (genomics) to individualize medical care.
1.IntroductionWhat is it?
Precision Medicine
Douglas Riegert-Johnson, MDAssistant Professor of Medicine and Medical GeneticsMayo Clinic Florida
Douglas Riegert-Johnson, [email protected] Clinic FloridaMedicine and Medical Genetics
2. IndicationsWho Needs It?
Visit
“I would like testing.”
“What type of testing?”
“Genetic testing”
”..for what.”“humm”
Indications For Genomic Testing • Expanded carrier
testing• History of stillbirths,
>2 miscarriages, previous child with SIDS
• Fam hx known genetic disorder
• Non invasive prenatal testing
• NGS panels for non-immune hydrops fetalis and other fetal anomalies
• Multiple congenital anomalies
• Autism• Intellectual Disability• Growth abnormalities• Hearing loss/
blindness• Muscle weakness
• Cancer syndromes• Cardiomyopathies• Diagnostic Odyssey• Adults with any
pediatric indication without a diagnosis
Pre-conception Prenatal
ChildhoodAdulthood
Indications for genetics referral: a guide for healthcare providers. Genetics in Medicine 2007
Preconception: ¼ individuals carries a recessive disease mutation
Lazarin et al. 2013 Genetics in Medicine 15(3) 178-186
Pre-conception
Resource: ACOG Preconceptual genetic testing.
Preconception testing gives couples information about their risk for having a child with a recessive condition (cystic fibrosis, fragile X).
Surprisingly, carrier rate is relatively high, disease is low. (Unlikely both partners are carrier for same disorder.)
Cystic fibrosis carrier rate = 1/25. Cystic fibrosis patient rate = 1/2500.
Preconception:¼ individuals carries a recessive gene trait
Commercially available genomic panel for 96 diseases
N=23,453 individuals tested
24% carriers for one disorder
5% carriers for > 2 disorders
Top 10 Most Common Carrier Frequencies A Alpha-1-Antitrypsin deficiency, cystic fibrosis, DFNB1, Spinal
muscular atrophy, Familial mediterranean fever, Smith-Lemli-Opitz syndrome, sickle cell disease/beta- thalassemia, Gaucher disease, Factor XI deficiency, achromatopsia
78 had a potentially diagnostic test result Included 18 different disorders, 2 of which specific genetic therapy
Lazarin et al. 2013 Genetics in Medicine 15(3) 178-186
Pre-conception
Non invasive prenatal testing (NIPT)is replacing amniocentesis
PrenatalAmniocentesis had been recommended for women > 35 yo for Down syndrome (trisomy 21) and other trisomies.
Prior to NIPT approx 200,000 amniocentesis performed per year.
Non invasive prenatal testing (NIPT)is replacing amniocentesis
Prenatal
From Nature
15% of circulating cell free DNA is placental. NIPT can be performed 10-22 weeks of pregnancy on a maternal blood sample.
2014 New England Journal of Medicine NIPT
NIPT is very accurate. Amniocentesis is now only used to confirm abnormal NIPT. So number of “amnios” has declined precipitously.
50,BCA dx @ 45 yo
d. 62, BCA dx @ 40 yo
d. 40, BCA dx @35 yo
222
Familial Breast Cancer, but BRCA ½ gene testing no mutation
= Breast cancer
Adulthood
BRCA1
BRCA2
ATM
BARD1MSH2MSH6 MLH1
PALB2
NF1
CHEK2
CDH1TP53
RAD50
PMS2
Genetics 2 genes $4200 12 weeks
Genomics 14 genes $2000 ($100) 4 weeks
BRCA1/2 negative: 10% will have + test result with
genomic testing.
30
62 40
2
Changes to medical care as a result of genomics:
Consider prophylactic mastectectomy. Pancreas cancer screening
22
Ref
Newsflash PALB2 Mutation found by genomics!
Genomics of drug metabolismAdulthood
Difficult to identify clinically relevant unambiguous pharmacogenic tests for common disorders and or common medications.
CYP2C19 pharmacogenetic enzyme and Clopidogrel US Food and Drug Administration recommends CYP2C19
genotyping for individualized antiplatelet management [Ref].
“The substantial heterogeneity and publication bias implies that personalized antiplatelet management based on genotyping is not supported by the currently available evidence.” Genetics in Medicine 2014
For depression, there was no difference in patients treated as usual compared to those treatment was
determined by pharmacogenomic testing.
Discovery Medicine 2013.
51 patients with depression
26 Treatment guided bypharmacogenomics
25 Treatment as usual
Precision Medicine
Douglas Riegert-Johnson, MDAssistant Professor of Medicine and Medical GeneticsMayo Clinic Florida
Kimberly Guthrie, MS [email protected] Mayo Clinic FloridaCertified Genomic Counselor
3. ImplementationWhat do I need to do?
What do I have to do?
Refer to a genomic counselor
Implementation: What do I have to do?PRESS THE BUTTON
How do I find a genomic counselor?www.nsgc.org
Drag picture to placeholder or click icon to add
Genomic Counseling as a specialty
Under Graduate 4 years + Post Graduate 2 years
Specialty Number
Internists 189,587
Family medicine specialists 114,000
Genomic counselors 3,200
Medical geneticists 1,509 (all time)
What happens after you “Press the Button?”
Genomic Vitals: Obtain three generation family history
Formulate testing strategy based on personal and family history Who to test? What test(s) to do?
Pre-test counseling: review potential outcomes and implications of each outcome. If positive, what does that mean…
Coordination of testing and billing
Post-test counseling for results disclosure and discussion
Hypertrophic Cardiomyopathy:Most Common Familial Heart Disease 1:500
Average Primary Care Practice
N=2300
HCM N=4-5
FDR N = about 15
~16 Genes Described
Genomic panels are widely available
Disease causing mutations found in: 50-60% of familial cases 20-30% of cases with
no family history
Genomic Vitals: Mr. Mayport 48 years old with hypertrophic cardiomyopathy
48
HCM N Normal echo ? Echo status
unknown
d. 39 SCD
d. 70spneumonia
44
25 18
6568
NN
? ??
Formulate testing strategy
Insert screenshot of GeneTests search
>70 labs>200 single gene tests>50 panels
Pre-test counseling – Discussion of Potential Outcomes and
Implications
Positive Family:
Testing to determine need for screening
Testing for reproductive risk assessment
Personal: Syndromic or isolated Treatment implications
and additional referrals Prenatal diagnostic
options available
44
25 18
6568
NN
Pre-test counseling – Discussion of Potential Outcomes and Implications
Negative Personal:
Follow-up with Genomics in future for updates on testing
Reproductive testing not available
Family: Continue clinical
screening as recommended by guidelines
Genetic testing not useful for unaffected relatives
44
25 18
6568
NN
Pre-test counseling – Discussion of Potential Outcomes and Implications
Inconclusive Personal:
Follow-up annually for updates on variant interpretation and testing in general
No prenatal testing available
Family: Continue clinical screening May test other affected
family members Genetic testing for
unaffected family members is not recommended
44
25 18
6568
NN
Coordination of testing
Order testing
Arrange for specimen collection
Discussion of insurance coverage Requires knowledge of lab’s billing policies Obtain preauthorization for testing if necessary
Track results
Arrange for follow-up visit
Mr. M found to have MYH7 gene mutation
44
6568
NN
+ MYH7 mutation
+ MYH7 MutationNormal echoFollow up needed
No MYH7 mutationNormal echoNo follow up needed
25 18
Daughter is referred to GC for preconception counseling
Genomic vitals for daughter and her partner completed Partner’s family history unremarkable for single gene
disorders
Reproductive options for known MYH7 mutation reviewed: CVS Amniocentesis Preimplantation Genetic Diagnosis (PGD)
Expanded carrier testing offered for other diseases
Reproductive options for the daughter.
Pre implantation genetic diagnosis: Screening embryos for genetic disease
Results: Expanded Carrier Testing
Results: Expanded Carrier Testing
Family Outcomes
MYH7 mutation identified and used to determine which family members need continued HCM clinical screening
Identification of CF carrier in family also important for reproductive risks for other family members
Multiple reproductive options available for MYH7 mutation carriers
Big Hero Six : TEAMWORKPCP and Genomic counselors!
Pearls
Genetics Genomics = (testing many genes at once)
Precision medicine is the use of genomics to individualize medical care.
Genomic counseling is a recognized, boarded specialty. A directory of genetic counselors is available at nsgc.org.