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 1

2. You’ve met one individual with 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

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. 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

8. 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 autism risk loci
Oroak et al, 2012, Nature

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

10. 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

11. 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

12. 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

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

14. From State & Sestan 2012
From State & Sestan, 2012

15. SCN2A

16. 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

17. 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.

18. 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

19. Extra Slides

20. 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

21. 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.

22. Similar presentation 22

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