Download The Importance of Genetic Testing

.
The Importance of
Genetic Testing
• June 25-27, 2009
PPMD Connect Conference
• Vanessa Rangel Miller, MS, CGC
• [email protected]
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Overview
Genetics &Testing
Benefit & Limitations
Testing Pathway
Family Scenarios
Genetics & Inheritance
Genetics
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Xp21.2
Largest gene in human body
Spans ~2.2 MB or ~0.1% of genome
cDNA transcript is ~14kb
79 exons (0.6% of gene)
Large introns constitute 99.4% of gene
8 promoters
DMD
X chromosome
Genes
www.genetics.au.edu
exon
Deletions/Duplications
Gene
Deletion
Duplication
Point Mutations
Gene
C
A
T
C
A
T
Mutation
C
C
A
T
C
A
T
C
A
T
C
A
A
T
T
G
A
T
C
A
T
X ……
Nonsense Mutation
C
A
T
G
-
-
A
T
C
A
T
C
A
T
Frameshift Mutation
Gene Mutation Spectrum
Duchenne
Becker
~60-65%
~85%
Duplications
5-10%
5-10%
Small mutations
(insertions, deletions,
nonsense, splice, etc.)
30-35%
5-10%
Deletions
• 2/3 mutations maternally inherited
• 1/3 apparently de novo
(includes germline mosaicism)
Genetic Counseling
X-linked inheritance
– 2/3 carriers
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1 in 4 affected male
1 in 4 normal male
1 in 4 carrier female
1 in 4 non-carrier female
– 1/3 non-carriers
• ~15-20% recurrence in future pregnancies
• Maternal and paternal origin reported
• Review family history with care provider
• Aids medical management
• Contributes to testing of additional relatives
Genetic Testing
Benefits & Limitations
• Confirms the clinical
diagnosis
• Minimal procedure risk
• Family members
– Improve risk
assessment
– Diagnosis, reassurance
• Research studies & clinical
trials
• May require multiple tests
• May not identify a
mutation
• Unexpected results
• May not indicate
prognosis/severity
• Cost & time for results
What should I ask?
• How can my child be
tested?
– Blood sample
– Medical care provider or
genetics clinic
• How does my provider
order testing?
• What should I know
before the test is
ordered?
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Method
Detection
Cost
Insurance & Billing
Turnaround time
Possible results
Next steps
Genetic Test Pathway
Following Clinical Exam and CK:
1 - Test for Exon Deletions/Duplications
Method
Multiplex PCR
– Specific exon deletions
Southern
- Exon deletions & some duplications
Quantitative PCR
- Exon deletions & duplications
MLPA
- Exon deletions & duplications
Dystrophin Array CGH
- Exon deletions & duplications
Genetic Testing Pathway
2 - Test for Point Mutations
Method
Mutation Scanning (DDGE, SSCP, DHPLC)
-Scans coding region for potential sequence changes
- Followed by sequencing to identify the specific change
Sequence Analysis
- Determines sequence for coding region
Resequencing Array
-Array (chip) based sequencing
- Includes known intronic mutations
Genetic Testing Pathway
3 – Other test options
Method
Target
Comment
SCAIP
Combines testing for large
& small deletions, point
mutations
• Separate test for
duplications
Targeted/familial
mutation testing
Tests for small mutation
identified in family
Functional test for rare
mutations
• Requires knowledge of
mutation in family
mRNA / cDNA
Linkage
Tests regions in/near gene
(does not test mutation)
• Requires muscle biopsy
•May require 1+ males
with DMD
•Risk of recombination
Reading the Results
y Your doctor may interpret your results
y What does it mean if a mutation is found
y Mutation not found
y Variant?
y What your results will not tell you
y Prognosis
y Variability
y How to use results in a meaningful way for your family
y Compare with your family tree
Family Testing
Family Member Testing
• A del/dup is known in the family
– Use method reliable to identify the mutation
• A small/point mutation is known in family
– Targeted sequence analysis
• No mutation known
– Follow comprehensive test pathway
• Defer asymptomatic carrier testing in minors
Family Scenarios – Carrier Testing
• Pedigree
– Obligate carrier females
– Females with no family history
• Carrier
• Germline mosaicism
• De novo mutation
– Sisters may be at risk to be carriers
• Offered carrier testing & genetic counseling
• Carrier/confirmation testing
– Aid medical management
– Contributes to testing of additional relatives
What do I do?
Ask for a copy of your test results!
Questions to discuss with your doctor:
– I had a muscle biopsy, do I need genetic testing?
– No mutation was found, do I need more testing?
– Participated research testing, do I need other testing?
– Had testing in the past, should I be re-tested?
Who else can help?
DuchenneConnect!
Summary
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What to consider before genetic testing
Comprehensive test pathway
What results mean for you and your family
Future medical therapies
• Registry Participation is IMPORTANT
– Better understand the associations between
genotype and phenotype
Acknowledgements
ƒ PPMD
ƒ Pat Furlong
ƒ Giovanna Spinella
ƒ Kim Galbraith
ƒ Ryan Fischer
ƒ Brian Denger
ƒ Innolyst, Inc.
ƒ Kyle Brown
ƒ Cincinnati Children’s
ƒ Kathi Kinnett
ƒ Emory University
ƒ Yetsa Adadevoh
ƒ Andy Faucett
ƒ Ken Loud
ƒ Madhuri Hegde
ƒ NCHPEG
ƒ Holly Peay
ƒ DuchenneConnect Advisors
ƒ Our participants & families!