This proposal will explore the hypothesis that autism is caused by highly-penetrant, rare mutations using emerging technologies that screen regions for autism-specific copy- number variation (CNV) mutations and exonic point mutations. Our targeted focus will be 17 genomic regions (carrying 83 genes) and an additional 87 genes where copy-number changes and point mutations have been associated with autism. We propose three subprojects: 1) fine-scale CNV screening and validation to identify autism-specific structural changes;2) systematic assessment of high-impact point mutations in ~4000 coding exons using molecular inversion probe technology and next-generation sequencing;and 3) complete exome characterization of a subset of autism samples.
Aims 1 and 2 will be applied to 1320 simplex and multiplex families (AGRE and SFARI Simplex Collection), while the third aim will focus on the comprehensive assessment of 20 autism genomes. Our goal is to identify and characterize specific genes associated with autism and we anticipate that we will pinpoint the genetic causation of 5-10% of autism. This is an interdisciplinary effort that brings together cutting-edge technology in next-generation sequencing and CNV characterization to identify genes associated with autism.
This proposal will advance human health by developing a systematic strategy for the identification of mutations and genes associated with autism and it will optimize new technology for the characterization of patient genomes for pathogenic copy-number variation and point mutations associated with complex genetic disease. The diagnostic impact of this study is particularly high and will lead to the early diagnosis of children with molecular lesions and the genetic classification of different causes of autism. Such subcategorizations of autism will significantly enhance phenotypic characterization leading to future downstream treatments and interventions for autism.
|Wang, Qingyu; Shashikant, Cooduvalli S; Jensen, Matthew et al. (2017) Novel metrics to measure coverage in whole exome sequencing datasets reveal local and global non-uniformity. Sci Rep 7:885|
|He, Zongxiao; O'Roak, Brian J; Smith, Joshua D et al. (2014) Rare-variant extensions of the transmission disequilibrium test: application to autism exome sequence data. Am J Hum Genet 94:33-46|
|Krumm, Niklas; O'Roak, Brian J; Karakoc, Emre et al. (2013) Transmission disequilibrium of small CNVs in simplex autism. Am J Hum Genet 93:595-606|
|Girirajan, Santhosh; Dennis, Megan Y; Baker, Carl et al. (2013) Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am J Hum Genet 92:221-37|
|Chen, Ying-Zhang; Matsushita, Mark; Girirajan, Santhosh et al. (2012) Evidence for involvement of GNB1L in autism. Am J Med Genet B Neuropsychiatr Genet 159B:61-71|
|Girirajan, Santhosh; Rosenfeld, Jill A; Coe, Bradley P et al. (2012) Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N Engl J Med 367:1321-31|
|Veeramah, Krishna R; O'Brien, Janelle E; Meisler, Miriam H et al. (2012) De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet 90:502-10|
|O'Roak, Brian J; Vives, Laura; Girirajan, Santhosh et al. (2012) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:246-50|
|O'Roak, Brian J; Vives, Laura; Fu, Wenqing et al. (2012) Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338:1619-22|
|Krumm, Niklas; Sudmant, Peter H; Ko, Arthur et al. (2012) Copy number variation detection and genotyping from exome sequence data. Genome Res 22:1525-32|
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