Sporadic point mutations and large copy number variants (CNVs) contribute significantly to the etiology of autism but relatively few genes have been proven to be pathogenic. The goal of this project is to identify genes responsible for autism spectrum disorder (ASD) and developmental delay. We will apply an integrated approach combining exome sequence data and detailed ab initio CNV analysis to pinpoint likely candidate genes. We will test these candidates for an excess of de novo disruptive mutations in case versus control trios. There are three specific aims: 1) Expand our existing CNV morbidity map to include data from >40,000 cases of developmental delay versus 20,000 controls and integrate these data with emerging exome data to identify likely haploinsufficient genes;2) Assess whether the burden of disruptive de novo mutations in these genes is significantly enriched in ASD families by molecular inversion probe (MIP) resequencing of approximately 6,200 cases and 6,200 controls;and 3) Select ten genes with the highest burden of de novo mutations for further clinical evaluation, phenotypic variability, and comprehensive genetic characterization. The end product of this analysis will be the identification and characterization of highly penetran genic mutations that contribute significantly to etiology of autism, providing targets for clinical diagnostics and future therapeutics.

Public Health Relevance

This study integrates two common genetic risk factors (copy number variation and point mutations) of autism and developmental delay to pinpoint likely disease-causing genes. We will test the significance of sporadic loss-of-function mutations in these genes by applying cutting-edge genomic technologies to examine large numbers of families with autism. We will select a subset of genes and families for clinical follow-up to determine if there are common features and whether the mutations are necessary and sufficient to cause disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH101221-01
Application #
8558590
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Addington, Anjene M
Project Start
2013-08-01
Project End
2017-06-30
Budget Start
2013-08-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$713,231
Indirect Cost
$251,593
Name
University of Washington
Department
Genetics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Wang, Tianyun; Guo, Hui; Xiong, Bo et al. (2016) De novo genic mutations among a Chinese autism spectrum disorder cohort. Nat Commun 7:13316
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Duyzend, Michael H; Eichler, Evan E (2015) Genotype-first analysis of the 16p11.2 deletion defines a new type of "autism". Biol Psychiatry 77:769-71
Snyder, Matthew W; Simmons, LaVone E; Kitzman, Jacob O et al. (2015) Copy-number variation and false positive prenatal aneuploidy screening results. N Engl J Med 372:1639-45

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