Genetic Testing and Registries
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Transcript of Genetic Testing and Registries
Back to the Basics: Gene/c Tes/ng & Registries
PPMD Connect Conference June 2010 Vanessa Rangel Miller, MS, CGC
Overview
• Gene/cs &Tes/ng • Benefit & Limita/ons
• Tes/ng Pathway • Family Scenarios
• Registry Par/cipa/on
GENETICS & INHERITANCE
Gene/cs
– 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 cons/tute 99.4% of gene – 8 promoters
DMD
Genes
www.gene/cs.au.edu
exon
Dele/ons/Duplica/ons
Gene
Deletion Duplication
Point Muta/ons
C G A A G C
T G A A G C
C G A A G C C G A A G C
C G A - G C C G A A G C
A
Gene
Mutation
Nonsense Mutation
Frameshift Mutation
X ……
Gene Muta/ons
• 2/3 muta/ons maternally inherited • 1/3 apparently de novo
(includes germline mosaicism)
Duchenne Becker Deletions ~60-65% ~85%
Duplications 5-10% 5-10%
Small mutations (insertions, deletions, nonsense, splice, etc.)
30-35% 5-10%
Gene/c Counseling
X-‐linked inheritance – 2/3 carriers
• 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 tes/ng of addi/onal rela/ves
GENETIC TESTING
Benefits & Limita/ons
• Confirms the clinical diagnosis
• Minimal procedure risk • Family members
– Improve risk assessment
– Diagnosis, reassurance • Research studies & clinical
trials
• May require mul/ple tests
• May not iden/fy a muta/on • Unexpected results • May not indicate prognosis/
severity
• Cost & /me for results
What should I ask?
• How can my child be tested? – Blood sample – Medical care provider
• How does my provider order tes/ng?
• What should I know before the test is ordered?
– Method
– Detec/on – Cost – Insurance & Billing – Turnaround /me
– Possible results – Next steps
Gene/c Test Pathway Following Clinical Exam and CK:
Step 1 – Test for Exon Deletions/Duplications MLPA
- Exon deletions & duplications Dystrophin Array CGH
- Exon deletions & duplications Quantitative PCR
- Exon deletions & duplications Multiplex PCR
– Specific exon deletions Southern
- Exon deletions & some duplications
Gene/c Tes/ng Pathway
Step 2 Test for Point Mutations Sequence Analysis
- Determines sequence for coding region
Mutation Scanning (DDGE, SSCP, DHPLC) - Scans coding region for potential sequence changes - Followed by sequencing to identify the specific change
SCAIP - Combines testing for large & small deletions, point mutations - Separate test for duplications
Gene/c Tes/ng Pathway
Method Target Comment Targeted/familial mutation testing
Tests for small mutation identified in family
• Requires knowledge of mutation in family
mRNA / cDNA Functional test for rare mutations
• Requires muscle biopsy
Linkage Tests regions in/near gene (does not test mutation)
• May require 1+ males with DMD • Risk of recombination
Other test options
Reading the Results
• Your doctor may interpret your results
• What does it mean if a muta/on is found • Muta/on not found
• Variant? • What your results will not tell you
• Prognosis • Variability
• How to use results in a meaningful way for your family
• Compare with your family tree
FAMILY TESTING
Family Member Tes/ng
• A del/dup is known in the family – Use method reliable to iden/fy the muta/on
• A small/point muta/on is known in family – Targeted sequence analysis
• No muta/on known – Follow comprehensive test pathway
• Defer asymptoma/c carrier tes/ng in minors
Family Scenarios – Carrier Tes/ng
• Family history – Obligate carrier females
– Females with no family history • Carrier • Germline mosaicism
• De novo muta/on
– Sisters may be at risk to be carriers • Offer carrier tes/ng & gene/c counseling
• Carrier/confirma/on tes/ng – Aid medical management
– Contributes to tes/ng of addi/onal rela/ves
What do I do?
Ask for a copy of your test results!
Ques/ons to discuss with your doctor:
– I had a muscle biopsy, do I need gene/c tes/ng?
– No muta/on was found, do I need more tes/ng? – Par/cipated research tes/ng, do I need other tes/ng? – Had tes/ng in the past, should I be re-‐tested?
Who else can help?
JOIN A REGISTRY! What else can I do?
Registry Par/cipa/on
Why Join?
Medical information
Population size
Trial planning
Trial recruitment
Research Advances
Learn from others
Community interest
I’m registered, now what?
• Explore the site, learn from others • Keep your account up-‐to-‐date
– Send in your test results • Watch for emails
• Encourage others to join – Help advance research & future treatment for the community
Summary
• What to consider before gene/c tes/ng
• Comprehensive test pathway • What results mean for you and your family
• Future medical therapies
• Registry Par/cipa/on is IMPORTANT – Beoer understand the associa/ons between genes & disease
Acknowledgements PPMD
Pat Furlong Holly Peay Kim Galbraith
Ryan Fischer Brian Denger
Innolyst, Inc. Kyle Brown
Emory University Yetsa Adadevoh Andy Fauceo Ken Loud Pat Olney Madhuri Hegde
DuchenneConnect advisors Our parJcipants & families