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  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

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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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).

 

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

Alabama  

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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  

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Georgia  

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Illinois   Indiana  

Iowa  

Kansas  Kentucky  

Louisiana  

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Montana  

Nebraska  Nevada  

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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).