Genetics of Autism Spectrum Disorder (ASD) · Genetics of Autism Spectrum Disorder (ASD) Matthew W. State MD, PhD Oberndorf Family Distinguished Professor and Chairman Department

Genetics of Autism Spectrum Disorder (ASD)

Matthew W. State MD, PhD

Oberndorf Family Distinguished Professor and Chairman

Department of Psychiatry

Langley Porter Psychiatric Institute

Weill Institute for Neuroscience

University of California, San Francisco

De novo, likely-gene-disrupting (LGD) mutations in ASD vs Sib (WES)

Iossifov, Sanders et al Nature 2014

Natural selection has limited window to act on high-effect mutations

Germ-line de novo mutations

Affected offspring

Mutation in egg or sperm before fertilization

ASD

Unaffected

Sanders et al Nature 2012

Multiple de novo mutations per person in ASD versus Sib (WES)

ASD

Sib

De novo rate in ASD vs Sib (WGS)

Werling et al unpublished 2017

Sanders et al Nature 2012 Neale et al Nature 2012 O’Roak et al Nature 2012

De Rubeis et al Nature 2014 Iossifov et al Nature 2014 Sanders et al Neuron 2015

Stephan Sanders

ASD genes point to the synapse and chromatin modification

Figures by Montana Morris and Sarah Pyle

Temporal-spatial transcriptional profiling highlights mid-fetal human cortical development in ASD risk

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windows of time

birth

ASD gene enrichment

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State and Sestan Science 2012 Willsey et al Cell 2013 Parikshak et al Cell 2013

Nenad Sestan

Jeremy Willsey

Illuminating the biology of ASD

• De novo mutations in sequence and structure of DNA carry large risks (more than 20X) for ASD;

• Genes are not fate. The risk is not specific: mutations may also confer risk for epilepsy, intellectual disability, schizophrenia, specific language impairment…;

• Genic large-effect mutations provide novel avenues to explore molecular, cellular and circuit level dysfunction in ASD and other neurodevelopmental disorders.