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

3. High resolution karyotype

5. Advantages Advantages “Whole genome scan” “Whole genome scan” Relative low cost Relative low cost Disadvantages Disadvantages Labor intensive Labor intensive Detection above 5 Mb Detection above 5 Mb

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

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

9. Microdeletion Detection

11. FISH Analysis

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

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

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

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

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

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

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

21. High Density Oligo CGH

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

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

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

29. Balanced Translocation

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

31. Overview of the Conference Talks Talks Assessments Assessments

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

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

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

35. 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

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

37. 7 th Annual International 11q Conference San Diego, CA July, 2010 Management 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

38. 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

39. Jessica Fekete (11q mom) Understanding Behavior issues Understanding Behavior issues

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

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

42. JACOBSEN’S and the EYE

43. 7 th Annual 11q Conference MusicWorx Inc. MusicWorx Inc. Music Therapy

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

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

46. 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). 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 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). 3). Dr. Zsuzsanna Bata-Csörg: Dermatologist (on site assessments with Dr. Mattina). 4). Dr. Neil Tipnis (questionnaire???) 4). Dr. Neil Tipnis (questionnaire???)

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