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 1

You’ve met one individual with autism… The importance of parsing the heterogeneity

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

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

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

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

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

Exome Sequencing in Autism Oroak et al, 2012, Nature

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

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

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

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

From State & Sestan 2012 From State & Sestan, 2012

SCN2A

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

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.

Thank you SFARI To the families! SIMONS FOUNDATION AUTISM RESEARCH INITIATIVE 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

Extra Slides

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

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.

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Expert clinicians don’t agree ASD diagnoses by site (n = 2,102) ‏ Lord et al. 2012. Arch Gen Psychiatry