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 #
4R01MH101221-04
Application #
9096891
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Addington, Anjene M
Project Start
2013-08-01
Project End
2017-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Washington
Department
Genetics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Turner, Tychele N; Eichler, Evan E (2018) The Role of De Novo Noncoding Regulatory Mutations in Neurodevelopmental Disorders. Trends Neurosci :
Arnett, Anne B; Rhoads, Candace L; Hoekzema, Kendra et al. (2018) The autism spectrum phenotype in ADNP syndrome. Autism Res 11:1300-1310
Cheng, Hanyin; Dharmadhikari, Avinash V; Varland, Sylvia et al. (2018) Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies. Am J Hum Genet 102:985-994
Arnett, Anne B; Cairney, Brianna E; Wallace, Arianne S et al. (2018) Comorbid symptoms of inattention, autism, and executive cognition in youth with putative genetic risk. J Child Psychol Psychiatry 59:268-276
Guo, Hui; Wang, Tianyun; Wu, Huidan et al. (2018) Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Mol Autism 9:64
Van Dijck, Anke; Vulto-van Silfhout, Anneke T; Cappuyns, Elisa et al. (2018) Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP. Biol Psychiatry :
Jansen, Sandra; Hoischen, Alexander; Coe, Bradley P et al. (2018) A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency. Eur J Hum Genet 26:54-63
Earl, Rachel K; Turner, Tychele N; Mefford, Heather C et al. (2017) Clinical phenotype of ASD-associated DYRK1A haploinsufficiency. Mol Autism 8:54
Kim, Daniel Seung; Burt, Amber A; Ranchalis, Jane E et al. (2017) Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder. Am J Med Genet B Neuropsychiatr Genet 174:381-389
Wilfert, Amy B; Sulovari, Arvis; Turner, Tychele N et al. (2017) Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications. Genome Med 9:101

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