Introduction to Genetics and Overview of the Conference

1. Introduction to Genetics and Overview of the Conference Paul Grossfeld, M.D. Associate Adjunct Professor UCSD School of Medicine July 7, 2010

2. High resolution karyotype

4. High resolution karyotype • Advantages • “Whole genome scan” • Relative low cost • Disadvantages • Labor intensive • Detection above 5 Mb

5. FISH Methodology • Www.nhgri.nih.gov./DIR/VIP (Artist Darryl Leja)

7. FISH Analysis • Advantages • Highly specific (100 kb) • Microdeletions/Microduplications • Disadvantages • Highly specific • 500-600 probes needed to match the power of karyotyping

8. Microdeletion Detection

9. Microdeletion Detection

10. FISH Analysis

11. To improve detection… • G-banding alone is insufficient to identify clinically significant deletions/duplications • Additional molecular cytogenetic technologies are needed that offer a whole genome approach to submicroscopic imbalances

12. Array-based Comparative Genomic Hybridization • Molecular cytogenetic method to detect copy number imbalances • Capable of genome wide scanning • Less labor intensive • Objective method compared to routine cytogenetic G-banding and FISH analysis

14. Methods • Isolate Genomic DNA from samples • DNA digestion • Label patient and control samples • Hybridize to microarray • Post hybridization washing • Assay scanning and data analysis

15. Array Design • Resolution depends on clone size and spacing • Only detect unbalanced rearrangements • Creates a “molecular karyotype”

16. Indications - Postnatal • Multiple congenital anomalies • Developmental delay/ mental retardation of unknown origin • Autism • Any individual suspected of a chromosomal imbalance, even with normal karyotype • High resolution mapping to identify specific genes

17. Assay Requirements • Each laboratory must define criteria for an abnormal result • Confirmatory testing by G-banding or FISH analysis • Parental testing often needed to interpret significance of results

19. Array FormatsHigh Resolution • 1-3 Mb spacing across the genome • 50 – 75 kb resolution • Oligonucleotides used to cover the genome • Approximately 50,000 clones • Numerous polymorphisms identified

20. High Density Oligo CGH

21. Characterization of known cytogenetic rearrangements to determine size and gene content

22. Approximately 10% imbalances detected in individuals with normal karytoype

27. Definition of 11q Terminal Deletion Disorder • Terminal Deletion in 11q • Either sporadic (normal parents, 90-95%) or inherited (from a parent with a balanced translocation, 5-10%) • Can be an Inte ial Deletion (very rare) • NOT an noisrevnI • NOT a BalancedTranslocation/Balanced Translocation • NOT a Duplicaplication

28. Balanced Translocation

29. Mechanisms of 11q- deletions • Variation in deletion size • All breakpoints cluster around CCG repeats • The largest deletions are caused by CCG repeat expansion/Fra11B fragile site • Smaller deletions: Not associated with a fragile site • All of the smallest deletions are derived from the paternal chromosome

30. Overview of the Conference • Talks • Assessments

31. Dr. Sarah Mattson • Review of what we have learned about your 11q children • Rationale and logistics of the assessments • What we hope to learn and how this can help your child

32. Traditional Osteopathic Medicine Kathryn Gill, M.D.

33. The effects of Neurogranin on learning and memory in 11q- Andras Bratincsak, MD, PhD July 8th, 2010

34. The ETS-1 gene and heart defects in 11q-: Clinical implications Paul Grossfeld, M.D. Associate Adjunct Professor UCSD/Rady Children’s Hospital of San Diego July 8, 2010

35. Dr. Teresa Mattina • The natural history of Jacobsen syndrome: A comprehensive analysis of the physical findings in JS

36. 7th Annual International 11q ConferenceSan Diego, CA July, 2010Management of Behavior Problems in Children with Developmental Delay Martin T. Stein MD Division of Child Development and Community Health Department of Pediatrics University of California San Diego Rady Children’s Hospital

37. Autism: Separating facts from myths and what you need to know about your child Natacha Akshoomoff, Ph.D. Department of Psychiatry, University of California, San Diego Child & Adolescent Services Research Center and Developmental Services Rady Children's Hospital, San Diego Conflict of Interest: None

38. Jessica Fekete (11q mom) • Understanding Behavior issues

39. Endocrine Aspects of 11qIs there a role for GH? …no issue Small Thomas G. Kelly, MD, FAAP Pediatric Endocrinology UC San Diego / Rady Children’s Hospital San Diego

40. Dr. Neel Tipnis • Chronic constipation and other gastrointestinal problems (A fun and informative discussion about bowel movements!)

41. JACOBSEN’S and the EYE

42. Music Therapy 7th Annual 11q Conference MusicWorx Inc.

43. Bleeding in Paris-Trousseau syndrome 11q23 Family Conference July, 2010

44. Mr. Chuck Hehmeyer, Esq • Navigating the legal system to get what your 11q child needs

45. Clinical Assessments • 1). Dr. Mattina/Dr. Gillgopian (General, as well as blood draw for high resolution deletion mapping for those patients that have not yet had this done). • 2). Drs. Sarah Mattson/Natacha Akshoomoff (Cognitive/behavioral): Questionnaires and onsite testing at SDSU • 3). Dr. Zsuzsanna Bata-Csörg: Dermatologist (on site assessments with Dr. Mattina). • 4). Dr. Neil Tipnis (questionnaire???)

46. PROGRESS • FOURTEEN papers published since we started in 1997!!! • But MANY challenges still exist. • You, as parents, have a critical role and responsibility to help educate others about JS. It can literally save your child’s life!!!