DS360:

Establishing a comprehensive genotype 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 rreeves@jhmi.edu

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

The most common feature of Down syndrome (DS) is variability.

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 (Hirschsprungs, IBD, celiac disease.)

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.

The Down Syndrome Phenome Project

Genetic modifiers

Genetic modifiers

Genetic modifiers

Genetic modifiers

Genetic modifiers

Genetic modifiers

Genetic modifiers

Genetic modifiers

Genetic modifiers

Genetic modifiers

GWAS/ CNV/ WES/ WGS

Define phenotypes. Genome wide genetic analyses. Co-morbidities.

Google: DS heart project hopkins DSCP see Booth 42 at the convenAon

Genetic modifiers

The Down Syndrome Heart Project

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, Childrens National Medical Center6 and 5Emory University School of Medicine

NHLBI: R01 HL083300 http://inertia.bs.jhmi.edu/index.html Google: DS heart project hopkins

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 sucient to cause septal defects

How do we study this?

Collect the appropriate case and control subjects (400 aected + parents) Genome-wide analysis (GWAS, WES, WGS) Candidate gene analysis in DS and in non- syndromic AVSD (CRELD1) Mouse models to suggest and to conrm candidate genes, dene 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).

Google: Down syndrome cogni3on project See DS360 at booth 42 at NDSC!

Understanding the variability of cogni=on among individuals with Down syndrome

Currently 10 sites in the network
Oregon Health & Sciences University
Montana Idaho South Dakota Wyoming

Waisman Center
North Dakota Minnesota

Childrens Hospital of Philadelphia

New Wisconsin

M.I.N.D. Ins3tute

Nevada Utah Colorado

Nebraska

Iowa Illinois Indiana Ohio West Virginia Kentucky

Pennsylvania

Johns Hopkins University Kennedy Krieger Inst. Childrens Na3onal Medical Center (and INOVA Health Systems)

Kansas

Missouri

Virginia

North Carolina Arizona New Mexico Oklahoma Arkansas Mississippi Alabama Tennessee South Carolina Georgia

University of Arizona

Texas

Louisiana

Emory University (University of Arkansas Medical Center)

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Hawaii

Understanding the variability of cogni=on among individuals with Down syndrome

3 days only!
Oregon Health & Sciences University
Montana Idaho South Dakota Wyoming

Waisman Center
North Dakota Minnesota

Childrens Hospital of Philadelphia

New Wisconsin

M.I.N.D. Ins3tute

Nevada Utah Colorado

Nebraska

Iowa Illinois Indiana Ohio West Virginia Kentucky

Pennsylvania

Johns Hopkins University Kennedy Krieger Inst. Childrens Na3onal Medical Center (and INOVA Health Systems)

Kansas

Missouri

Virginia

North Carolina Arizona New Mexico Oklahoma Arkansas Mississippi Alabama Tennessee South Carolina Georgia

University of Arizona

Texas

Louisiana

Booth #42, NDSC

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Emory University (University of Arkansas Medical Center)

Hawaii

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, Childrens 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 zebrash 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

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).

Unknown follower of Jan Joest of LKalkar Oil on Wood Flemish school, ca. 1515 Metropolitan Museum of Art, NY