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State of the Science in Autism (on the path to precision medicine)

State of the Science in Autism (on the path to precision medicine). Raphael Bernier, PhD Professor, Department of Psychiatry Clinical Director, Seattle Children’s Autism Center Associate Director, Center on Human Development and Disability University of Washington.

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State of the Science in Autism (on the path to precision medicine)

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  1. State of the Science in Autism (on the path to precision medicine) Raphael Bernier, PhD Professor, Department of Psychiatry Clinical Director, Seattle Children’s Autism Center Associate Director, Center on Human Development and Disability University of Washington

  2. You’ve met one individualwith autism… The importance of parsing the heterogeneity

  3. The search for etiology… Collaborative Linkage Study of Autism Genome-Wide Associations MIP (molecular inversion probe) Sequencing 1999 2009 2013 ~5% of individuals 2007 2011 2012 2014 Full Scale Exome Sequencing De Novo Copy Number Variations Pilot Exome Sequencing CHD8 gene

  4. The search for etiology… Collaborative Linkage Study of Autism Genome-Wide Associations MIP (molecular inversion probe) Sequencing 1999 2009 2013 2007 2011 2012 2014 Full Scale Exome Sequencing De Novo Copy Number Variations Pilot Exome Sequencing CHD8 gene

  5. The search for etiology… Collaborative Linkage Study of Autism Genome-Wide Associations MIP (molecular inversion probe) Sequencing 1999 2009 2013 2007 2011 2012 2014 Full Scale Exome Sequencing De Novo Copy Number Variations Pilot Exome Sequencing CHD8 gene

  6. The search for etiology… Collaborative Linkage Study of Autism Genome-Wide Associations MIP (molecular inversion probe) Sequencing 1999 2009 2013 2007 2011 2012 2014 Full Scale Exome Sequencing De Novo Copy Number Variations Pilot Exome Sequencing CHD8 gene

  7. Exome Sequencing in Autism • Replicated exome study in 209 individuals with ASD • Identified disruptions to 248 neurologically expressed genes in 25% of the sample • Only 2 genes with recurrence: CHD8 (2 individuals) & NTNG1 (2 individuals) • Based on this number of disruptions, we can estimate there are 384-821 autism risk loci Oroak et al, 2012, Nature

  8. Exome Sequencing in Autism Oroak et al, 2012, Nature

  9. The search for etiology… Collaborative Linkage Study of Autism Genome-Wide Associations MIP (molecular inversion probe) Sequencing 1999 2009 2013 2007 2011 2012 2014 Full Scale Exome Sequencing De Novo Copy Number Variations Pilot Exome Sequencing CHD8 gene

  10. MIP Sequencing • Tested for disruption of the 44 network genes in over 2000 individuals with ASD. • Identified recurrent disruptions to these genes. • Links to specific phenotypes Oroak et al, 2012, Science

  11. The search for etiology… Collaborative Linkage Study of Autism Genome-Wide Associations MIP (molecular inversion probe) Sequencing 1999 2009 2013 2007 2011 2012 2014 Full Scale Exome Sequencing De Novo Copy Number Variations Pilot Exome Sequencing CHD8 gene

  12. The search for etiology… 16p11.2 CNV POGZ gene 1q21.1 CNV ADNP gene ~50% of individuals 2014 2014-2015 2015 2016 2014 2015 2014 2016 DYRK1A gene WAC gene Rare, inherited mutations CHD8 gene

  13. From State & Sestan, 2012

  14. SCN2A

  15. Clinical Implications • Provide “answers” for some families • Provide guidance for monitoring • E.G. GI and sleep for CHD8, seizures for 16p11.2, etc • Provide sense of community • E.G. Families SCN2A foundation, DYRK1A.org, 16p11.2 family group, CHD8 facebook community, etc • Link scientists to patient community • Guide targeted treatments • Medication trials already underway • Identify behavioral treatment responders

  16. Conclusion • Tremendous behavioral and genetic heterogeneity in ASD. • Genetically defined individuals reveal subtle but real behavioral subtypes. • By identifying genetic mechanisms we can • Develop targeted treatments (at multiple levels) • Develop biological markers that are linked to biology • Develop early detection tools to start intervention earlier • Provide immediate impacts for families • And…begin to provide the right support, for the right person, at the right time.

  17. Thank you To the families! To collaborators: Evan Eichler, Heather Mefford, Sara Webb, Scott Murray, Zoran Brkanac, Holly Stessman, Tychele Turner, Brian O’Roak, Autism Biomarker Consortium Team, Simons Simplex Collection Team, Simons VIP Team, SPARK Team SFARI SIMONS FOUNDATION AUTISM RESEARCH INITIATIVE

  18. Extra Slides

  19. Behaviorally Defined ASD • Presence or absence of behaviors in social communication and restricted/repetitive behaviors. • Wing and Gould classification: • Aloof, Active but odd, Withdrawn • DSM-IV: • Autistic Disorder, Asperger’s Syndrome, PDD-NOS • Behaviorally defined subtypes do not share similar etiology, specific treatment approaches, nor can they be reliably defined. • DSM-5: • Autism Spectrum Disorders

  20. Simons Simplex Collection • 12 site collaboration to identify genetic contributors to ASD. • Collected all measures in same manner with strict cross site reliability. • Strict guidelines and reliability measures for evaluative tools: • ADI • ADOS • Examine clinical diagnosis across sites where clinicians reliably use all measures, but haven’t established “clinical diagnosis” prototypes.

  21. Similar presentation

  22. Expert clinicians don’tagree ASD diagnoses by site (n = 2,102) ‏ Lord et al. 2012. Arch Gen Psychiatry

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