genetics of autism spectrum disorder (asd) · genetics of autism spectrum disorder (asd) matthew w....
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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Werling et al unpublished 2017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
clu
ster
s o
f h
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an b
rain
reg
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windows of time
birth
ASD gene enrichment
?
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.