Introduction to Genetics and Overview of the ConferencePaul Grossfeld, M.D.Associate Adjunct ProfessorUCSD School of MedicineJuly 7, 2010

High resolution karyotype

High resolution karyotypeAdvantagesWhole genome scanRelative low costDisadvantagesLabor intensiveDetection above 5 Mb

FISH MethodologyWww.nhgri.nih.gov./DIR/VIP (Artist Darryl Leja)

FISH AnalysisAdvantagesHighly specific (100 kb)Microdeletions/MicroduplicationsDisadvantagesHighly specific500-600 probes needed to match the power of karyotyping

Microdeletion Detection

Microdeletion Detection

FISH Analysis

To improve detectionG-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

Array-based Comparative Genomic Hybridization

Molecular cytogenetic method to detect copy number imbalancesCapable of genome wide scanningLess labor intensiveObjective method compared to routine cytogenetic G-banding and FISH analysis

MethodsIsolate Genomic DNA from samplesDNA digestionLabel patient and control samplesHybridize to microarrayPost hybridization washingAssay scanning and data analysis

Array DesignResolution depends on clone size and spacing

Only detect unbalanced rearrangements

Creates a molecular karyotype

Indications - PostnatalMultiple congenital anomaliesDevelopmental delay/ mental retardation of unknown origin AutismAny individual suspected of a chromosomal imbalance, even with normal karyotypeHigh resolution mapping to identify specific genes

Assay RequirementsEach laboratory must define criteria for an abnormal result Confirmatory testing by G-banding or FISH analysisParental testing often needed to interpret significance of results

Array FormatsHigh Resolution

1-3 Mb spacing across the genome50 75 kb resolutionOligonucleotides used to cover the genome Approximately 50,000 clonesNumerous polymorphisms identified

High Density Oligo CGH

Characterization of known cytogenetic rearrangements to determine size and gene content

Approximately 10% imbalances detected in individuals with normal karytoype

Definition of 11q Terminal Deletion DisorderTerminal Deletion in 11qEither 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 noisrevnINOT a Balanced Translocation/Balanced TranslocationNOT a Duplicaplication

Balanced Translocation

Mechanisms of 11q- deletionsVariation in deletion sizeAll breakpoints cluster around CCG repeatsThe largest deletions are caused by CCG repeat expansion/Fra11B fragile siteSmaller deletions: Not associated with a fragile siteAll of the smallest deletions are derived from the paternal chromosome

Overview of the ConferenceTalksAssessments

Dr. Sarah MattsonReview of what we have learned about your 11q childrenRationale and logistics of the assessmentsWhat we hope to learn and how this can help your child

Traditional Osteopathic Medicine

Kathryn Gill, M.D.

The effects of Neurogranin on learning and memory in 11q- Andras Bratincsak, MD, PhDJuly 8th, 2010

The ETS-1 gene and heart defects in 11q-: Clinical implications Paul Grossfeld, M.D.Associate Adjunct ProfessorUCSD/Rady Childrens Hospital of San DiegoJuly 8, 2010

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

7th Annual International 11q ConferenceSan Diego, CA July, 2010

Management of Behavior Problems in Children with Developmental DelayMartin T. Stein MDDivision of Child Development and Community HealthDepartment of Pediatrics University of California San DiegoRady Childrens Hospital

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 DiegoChild & Adolescent Services Research Center andDevelopmental ServicesRady Children's Hospital, San Diego

Conflict of Interest: None

Jessica Fekete (11q mom)Understanding Behavior issues

Endocrine Aspects of 11qIs there a role for GH?

no issueThomas G. Kelly, MD, FAAPPediatric Endocrinology UC San Diego / Rady Childrens Hospital San Diego

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

JACOBSENS and the EYE

7th Annual 11q Conference MusicWorx Inc.Music Therapy

Bleeding in Paris-Trousseau syndrome11q23 Family ConferenceJuly, 2010

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

Clinical Assessments1). 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 SDSU3). Dr. Zsuzsanna Bata-Csrg: Dermatologist (on site assessments with Dr. Mattina).4). Dr. Neil Tipnis (questionnaire???)

PROGRESSFOURTEEN 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!!!

*A unique approach to medical care .change limitations imposed by infectious, traumatic, genetic, environmental or surgical processes.*