Cerebral palsy genomics update Michael Kruer, MD CPRN Site PI, Phoenix Chair, International Cerebral Palsy Genomics Consortium CPRN Houston Investigators Meeting May 31-June 1, 2018

Aims & Hypotheses Identify genetic causes of CP Why would we want to do that? Challenge dogma- are we digging in the wrong place? Precision Medicine: diagnosis & prognosis Guide family planning Preventative healthcare Specific treatments Better apply the tools we have

Who is doing this?

Methods Recruit 500 parent-child trios with cryptogenic CP from CPRN centers Enrollment via study coordinators; saliva collection kits (DNA source) Phenotyping via CPRN Data Coordinating Center Validate candidate CP genes in the laboratory using cell lines and fly knockout models

Patient/Advocacy Engagement “I just wanted to say how excited I am that you and your organisation are undertaking this project. For most of my life individuals with CP have been steeped in the narrative that there is very little to no ‘active’ science in CP and it made me feel very heartened (and a little emotional) to see that such care was being taken to investigate a very complex area.” Amy Hogan, CP researcher/advocate (Y. Wilson, unpublished; used with permission)

Patient-centered outcomes Questions Do children with genetic forms of CP differ from those with environmental forms of CP? If so, how? Can genetic forms of CP give us new insight into the disorder (as occurred in Parkinson and Alzheimer Disease)? Genetic findings from this study can be returned to participants if they so choose

Subject population and sample size All CPRN sites This R01 focuses on “cryptogenic” CP (without known cause) Sample size target: 500 families

Importance to CP community and fit with CPRN

Progress since concept review R01 initial submission June 2017 Reviewed but not funded Main critique #1: Statistical genomics analysis not robust enough Main critique #2: Validation studies are lacking Resubmission March 2018; in review Addressed critique #1 by adding Peter Jin (Yale) and Qiongshi Liu (U Wisc) Addressed critique #2 by adding validation studies initially proposed!

Call to action Opportunity for a 2nd R01 submission comparing the genomic basis of cryptogenic and environmental CP Both have a genetic basis! (Why do babies develop strokes or hemorrhages?!) Plans for R21 assessing response to SDR in genetically-defined subtypes of CP (overlap with hereditary spastic paraplegia)

Questions?