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. The Importance of Genetic Testing • June 25-27, 2009 PPMD Connect Conference • Vanessa Rangel Miller, MS, CGC • [email protected] 1 • • • • Overview Genetics &Testing Benefit & Limitations Testing Pathway Family Scenarios Genetics & Inheritance Genetics – – – – – – – 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 • • • • 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? – – – – – – – 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 • • • • 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 PPMD Pat Furlong Giovanna Spinella Kim Galbraith Ryan Fischer Brian Denger Innolyst, Inc. Kyle Brown Cincinnati Children’s Kathi Kinnett Emory University Yetsa Adadevoh Andy Faucett Ken Loud Madhuri Hegde NCHPEG Holly Peay DuchenneConnect Advisors Our participants & families!