Introduction to Genetics and Overview of the Conference

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					Introduction to Genetics and
 Overview of the Conference
        Paul Grossfeld, M.D.
     Associate Adjunct Professor
     UCSD School of Medicine
             July 7, 2010
High resolution karyotype
   High resolution karyotype
 Advantages

  “Whole   genome scan”
   Relative low cost

 Disadvantages

   Labor intensive

   Detection above 5 Mb
      FISH Methodology

 (Artist Darryl Leja)
             FISH Analysis
 Advantages
   Highly specific (100 kb)
   Microdeletions/Microduplications
 Disadvantages
   Highly specific
   500-600 probes needed to match
    the power of karyotyping
Microdeletion Detection
Microdeletion Detection
FISH Analysis
       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
    Array-based Comparative Genomic
   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
 Isolate Genomic DNA from samples
 DNA digestion

 Label patient and control samples

 Hybridize to microarray

 Post hybridization washing

 Assay scanning and data analysis
              Array Design
   Resolution depends on clone size and

   Only detect unbalanced rearrangements

   Creates a “molecular karyotype”
        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
      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
        Array Formats
       High Resolution
 1-3 Mb spacing across the genome
 50 – 75 kb resolution

 Oligonucleotides used to cover the
 Approximately 50,000 clones

 Numerous polymorphisms identified
High Density Oligo CGH
  Characterization of
  known cytogenetic
  rearrangements to
determine size and gene
  Approximately 10%
imbalances detected in
individuals with normal
       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 Balanced Translocation/Balanced Translocation
   NOT a Duplicaplication
Balanced Translocation
     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
   All of the smallest deletions are derived from the
    paternal chromosome
      Overview of the Conference
   Talks
   Assessments
            Dr. Sarah Mattson
   Review of what we have learned about your 11q
   Rationale and logistics of the assessments
   What we hope to learn and how this can help
    your child
Osteopathic Medicine

         Kathryn Gill, M.D.
The effects of Neurogranin
on learning and memory in
   Andras Bratincsak, MD, PhD
          July 8th, 2010
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
            Dr. Teresa Mattina
   The natural history of Jacobsen syndrome: A
    comprehensive analysis of the physical findings
    in JS
      7th 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
 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
       Jessica Fekete (11q mom)
   Understanding Behavior issues
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
               Dr. Neel Tipnis
   Chronic constipation and other gastrointestinal
    problems (A fun and informative discussion
    about bowel movements!)
JACOBSEN’S and the
Music Therapy

   7th Annual 11q Conference
      MusicWorx Inc.
Bleeding in Paris-Trousseau

    11q23 Family Conference
           July, 2010
      Mr. Chuck Hehmeyer, Esq
   Navigating the legal system to get what your 11q
    child needs
            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???)
   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!!!

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