roger reeves: ds360: establishing a comprehensive genotype phenotype study of down syndrome
DESCRIPTION
Basic Research Panel Presentation at Global Down Syndrome Foundation Research & Medical Care Roundtable on Thursday, July 18, 2013, at Children's Hospital Colorado. Roger Reeves, PhD, is Professor, Department of Physiology, Johns Hopkins University School of Medicine.TRANSCRIPT
DS360: Establishing a comprehensive genotype ßà phenotype study of Down syndrome.
Global Down Syndrome FoundaAon Research & Medical
Care Roundtable
Roger H. Reeves, Ph.D. Dept. of Physiology McKusick-‐Nathans InsAtute for GeneAc Medicine Johns Hopkins University School of Medicine [email protected] Stephanie Sherman, Ph.D. Dept. of GeneAcs Emory University School of Medicine
Funding: NICHD, Down Syndrome Research and Treatment Foundation (DSRTF), Research Down Syndrome (RDS), Anna and John J. Sie Foundation; Consultant to Roche Pharmaceutical, Elan Pharmaceutical; SAB: DSRTF, RDS, NDSS; Member,
Research Grants Council of Hong Kong
1. CogniAve ability 2. Alzheimer disease (age of onset, severity of
neuropathology, presence of demenAa) 3. Heart disease – yes/no, which structural
defects? 4. Sleep apnea – type, severity 5. Gut issues (Hirschsprung’s, IBD, celiac disease.)
The most common feature of Down syndrome (DS) is variability.
Working hypotheses: 1. Some of this variability has a geneAc basis. 2. The occurrence (severity) of one phenotype may be predicAve of other aspects of DS.
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GWAS/ CNV/ WES/ WGS
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Define phenotypes. Genome wide genetic analyses. Co-morbidities.
The Down Syndrome Phenome Project
Google: “DS heart project hopkins” “DSCP” see Booth 42 at the convenAon
NHLBI: R01 HL083300 http://inertia.bs.jhmi.edu/index.html Google: “DS heart project hopkins”
Roger Reeves1, Cheryl Maslen2, George Capone1,3, Ken Dooley5, Eleanor Feingold4, Ken Rosenbaum6,Tracie Rosser5, Michal Zwick5 and Stephanie Sherman5
1Johns Hopkins University School of Medicine, 2Oregon Health and Science University, 3Kennedy Krieger Institute, 4University of Pittsburgh, Children’s National Medical Center6 and 5Emory University School of Medicine
The Down Syndrome Heart Project
Congenital heart disease (CHD) • Occurrence, 1/100 live births (among the most frequent birth
defects in humans) • 50% of people with trisomy 21 have CHD (mostly septal
defects) – 50% have no clinical anomaly of the heart • Complete AVSD occurs in 1/10,000 euploid but 1/5 with DS • Trisomy 21 is a huge risk factor but is not sufficient to cause
septal defects
How do we study this? • Collect the appropriate case and control subjects (400 affected + parents)
• Genome-‐wide analysis (GWAS, WES, WGS) • Candidate gene analysis in DS and in non-‐syndromic AVSD (CRELD1)
• Mouse models to suggest and to confirm candidate genes, define eAology (trisomy models, septaAon mutants)
Google: “Down syndrome cogni3on project” See the “DS360”, booth 42 at NDSC!
Johns Hopkins-‐DSRTF/RDS/AJSF Virtual Research Center and Network
Goals: • Define cognitive phenotypes in Down syndrome (Edgin, Nadel).
• Virtual Center Network: Identify genetic factors that explain the variation in cognition as a basis to develop and test therapeutic approaches
• Create the Prototype for a Community-wide project to determine co-morbidities of penetrance and expressivity among DS phenotypes (DS360).
7
Google: “Down syndrome cogni3on project” See “DS360” at booth 42 at NDSC!
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0 0
Hawaii
Oregon Health & Sciences University
Waisman Center
Johns Hopkins University
Children’s Na3onal Medical
Center (and INOVA
Health Systems)
Emory University
University of Arizona
Currently 10 sites in the network
Understanding the variability of cogni=on among individuals with Down syndrome
Children’s Hospital of Philadelphia
M.I.N.D. Ins3tute
Kennedy Krieger Inst.
(University of Arkansas Medical Center) 8
Alabama
Arizona
Arkansas
Colorado
Georgia
Idaho
Illinois Indiana
Iowa
Kansas Kentucky
Louisiana
Minnesota
Mississippi
Missouri
Montana
Nebraska Nevada
New
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Pennsylvania
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South Dakota
Tennessee
Texas
Utah
Virginia West Virginia
Wisconsin
Wyoming
0 0
Hawaii
Oregon Health & Sciences University
Waisman Center
Johns Hopkins University
Children’s Na3onal Medical
Center (and INOVA
Health Systems)
Emory University
University of Arizona
3 days only!
Understanding the variability of cogni=on among individuals with Down syndrome
Children’s Hospital of Philadelphia
M.I.N.D. Ins3tute
Kennedy Krieger Inst.
(University of Arkansas Medical Center) 9
Booth #42, NDSC
Down Syndrome Face-Apnea-Cognition Project
Facial Morphology: Joan Richtsmeier, Penn State Univ.
(Increased fluctuating asymmetry in DS faces, JM Starbuck et al., online Pub March 2013)
Valerie DeLeon, Johns Hopkins Schl. Med.
Apnea: Sally Shott, Children’s Hospital of Cincinnati Stacey Ishman, Johns Hopkins Schl. Med. [Jamie Edgin, Univ. Arizona]
Cognition, Models, Genetics Core (DSCP): Jamie Edgin & Lynn Nadel, Arizona Roger Reeves, Hopkins Stephanie Sherman, Emory
Language acquisition: Len Abbeduto, M.I.N.D. Institute, CA U. Arizona Emory Hopkins/KKI
Laboratory
1. Resistance to solid tumors 2. SuscepAbility to congenital heart disease 3. A “cure” for cerebellar hypoplasia 4. Analysis of a Chromosome 21 gene expression library in zebrafish
5. New models to advance studies in Down syndrome
Sat., July 20, 8:30-‐10:00 Colorado Conven3on Center, Room 702
Basic research has changed the game for people with Down
syndrome.
Mouse model research directly underlies current clinical trials to improve cognition in
Down syndrome
Unknown follower of Jan Joest of LKalkar Oil on Wood Flemish school, ca. 1515 Metropolitan Museum of Art, NY
A.S. Levitas and C.S. Reid. An angel with Down syndrome in a sixteenth century Flemish naAvity painAng. Am. J. Med. Gen. 116A:399-‐405 (2003).