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IRP-Talk_ACHRDYS_030516
- 1. Can genetic screening enable definitive diagnosis of hormone resistance disorders? Tom Linton-Willoughby
- 2. ⇉ Acrodysostosis ACRDYS (AD) Skeletal - Brachydacytly (BDE) - Brachycephaly - Mid Facial Hypoplasia - Spinal Stenosis Endocrine - Hypothyroidism - Hypogonadism Spontaneous/de novo mutations Cognitive - Varying disability
- 3. Acrodysostosis ACRDYS (AD) difficult to distinguish from Albright’s Hereditary Osteodystrophy AHO (XR)
- 4. ACRDYS and AHO arise from defects in the PTH signal transduction pathway
- 5. »ACRDYS PDE4D: cAMP phosphodiesterase PRKAR1A: protein kinase A »AHO GNAS: encodes Gs α subunit
- 6. ACRDYS and AHO arise from defects in the PTH signal transduction pathway
- 7. Faults in Gs-α (AHO) or PRKAR1A (ACRDYS): “PTH resistance”
- 8. Fault in PDE4D (ACRDYS): “cAMP resistance”
- 9. Problem: ACRDYS and AHO produce clinically indistinct phenotypes How to diagnose? Project Aim: Establish national ACRDYS testing service at GOSH
- 10. » Approach - 11 patient cohort, negative for GNAS mutations - DNA extraction Chemagic Star - Spectrophotometry - PCR exons + flanking regions - Robotic bead + ethanol clean up - Sanger Sequencing - Mutation Surveyor - Alamut; PolyPhen2, ExAC, LOVD - Wincoot - ACGS Classification
- 11. » Results 17 variants detected within cohort 15 intronic variants • Found on LOVD, dbSNP, ESP, ExAC, low MAF • All Class 2 ACGS variants (unlikely pathogenic) 2 exonic variants, previously undocumented
- 12. Predicted – SIFT - Disease Causing - Mutation Taster - Disease Causing - PolyPhen2 - Probably Damaging c.934C>T p.(Leu312Phe) Het
- 13. Predicted - SIFT - Tolerated - Mutation Taster - Disease Causing - PolyPhen2 - Probably Damaging c.956T>C p.(Leu319Pro) Het
- 16. Project Aim: Establish national ACRDYS testing service at GOSH Outcomes: Screening service implemented on UKGTN Identified 2 previously unreported mutations in ACRDYS patients Confirmed ACRDYS-AHO clinical overlap and utility of genetic testing in distinguishing the conditions
- 17. Thanks! Any Questions? » Acknowledgements - Mrs Lucy Jenkins, Great Ormond Street Hospital, Genetics Laboratory - Ms Ann-Marie Differ, Great Ormond Street Hospital, Genetics Laboratory - Dr Richard Rayne, Birkbeck College, University of London (IRP Supervisor) - Prof Nicholas Keep, ISMB, Birkbeck College, University of London
Hinweis der Redaktion
- Former type styling of name looked OK on-screen, but probably will not project well. Student number not needed. Not crazy about the diagonal lines on the background…hard to tell how it will project. If too prominent, it will be distracting. I reset all to plain background.
- This is a good example of where revealing text bit-by-bit is useful. If all this went up at one time, a reader’s eyes will be zooming around the slide trying to make sense of it, and will not be hearing what you are saying. Acrodysostosis is a mouthful—needs to be displayed, on its own, first. Assume you will say “it may arise from…” first, then say something about each successive block.
- A bit awkward, perhaps. But emphasises the two conditions better than before, where they were both mentioned on the same slide. Allows you to go back to your key point: can molecular genetic analysis permit a definitive distinction between the two.
- Here, make the point as per the title and give a brief “tour” of the pathway. Next slide makes point re: which genes are implicated; next one after shows this picture again and zeros in on each affected protein.
- Use this as transition from the general description in preceding to “prime” the viewer for zooming in on these points in the pathway on the next slide. “The genetic faults here are…and...”
- I have animated the encircling lines with PDE4D first…you might want to alter the order. The idea is that you would say, for example: “Mutations in PDE4D block its effective action, preventing timely breakdown of cAMP and thus termination of the cAMP signal...” or something like this. Then, click to animate the circle on PRKAR1A, and make the comment you want to make there; then Gs-alpha. I colour-coded the circles—see next slide for why.
- This and next make point you previously made only in text. Better with graphic.
- Makes the “problem” and the “solution” far more emphatic than before. Before you state the aim, you can say “there is already AHO testing, but not ACRDYS testing…” Put the problem back to black text if you don’t like the red.
- Better to spread this out over multiple slides
- Explicitly reiterates the project aim…and lays out the outcomes against the aim on one slide.