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

2. Highresolutionkaryotype 3. 4. Highresolutionkaryotype

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)

6. 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-basedC omparativeG enomicH ybridization

Molecularcytogenetic method to detect copy number imbalances

Capable ofgenome widescanning

Less labor intensive

Objectivemethod compared to routine cytogenetic G-banding and FISH analysis

13. 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

18. 19. Array Formats High 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 23. 24. 25. 26. 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 Inteial Deletion (very rare)

NOT an noisrevnI

NOT aBalanced Translocation/BalancedTranslocation

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 8 th , 2010 34. The ETS-1 gene and heart defects in 11q-:Clinical implicationsPaul Grossfeld, M.D. Associate Adjunct Professor UCSD/Rady Childrens 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. 7 thAnnual International 11q Conference San Diego, CAJuly, 2010 Management of Behavior Problems in Children with Developmental Delay Martin T. Stein MD Division of Child Development and Community Health Department of PediatricsUniversity of California San Diego Rady Childrens 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 11q Is there a role for GH?noissue Thomas G. Kelly, MD, FAAP Pediatric EndocrinologyUC San Diego / Rady Childrens Hospital San Diego Small 40. Dr. Neel Tipnis

Chronic constipation and other gastrointestinal problems (A fun and informative discussion about bowel movements!)

41. JACOBSENS and the EYE 42. 7 thAnnual 11q Conference MusicWorx Inc. Music Therapy 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-Csrg: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 childs life!!!