Genetic and phenotypic heterogeneity in autism and autism spectrum disorders (ASD) pose significant challenges for research focused on defining biomarkers, developmental trajectory and treatment and outcomes. This provides a key rationale for requiring Fragile X testing and high resolution karyotyping using SNP arrays on all subjects enrolled in ACE Centers or Networks, as we will continue to in this ACE. In our previous ACE Center Project II, we hypothesized that studying ASD endophenotypes, would aid in identification of more homogeneous patient subgroups and hasten identification of genetic loci. We showed how a common ASD susceptibility variant in CNTNAP2 modulates brain function, connecting gene to brain to endophenotype for the first time in ASD. We also identified several cases of rare, large copy number variation (CNV) and smaller variants of less certain pathogenecity. Here we propose to continue to genetically characterize all ACE probands, hypothesizing that identifying certain etiological subclasses may provide more homogeneous populations that will be more predictive of trajectory and outcome. We will integrate identification of CNV with gene expression data to identify dysregulated genes within and near CNVs, thus improving classification of pathogenecity, and identify those with mutations currently undetectable by structural variant analysis alone. We will take a systems approach to functionally group these genes into biological pathways, and thus to group patients by shared molecular defects. We will then relate shared molecular pathway defects in the patient subsets to the phenotypic biomarker measurements collected in projects l-IV. We will test the relationship between known and newly discovered genetic variants and measures of behavior, eye-tracking/pupillometry, EEG, and brain imaging at both single time points and examining longitudinal trajectories, as well as their influence on response to treatment. In this way we seek to connect genetic variation to measures of brain function as a means of unraveling the genetic and phenotypic heterogeneity observed in ASD, and to develop improved predictors of diagnosis and treatment response.
Autism Spectrum Disorder varies widely in both symptoms and causes and perhaps is best thought of as the autisms. ASD has a strong genetic component, but the mutations causing disease are largely unknown. We will use genetic measures to define more homogeneous sub-types of autism so as to increase power in clinical trajectory and treatment studies, identify biomarkers and integrate genetic data with measures of behavior and brain function to identify biological processes that are disrupted in ASD.
|Di Martino, Adriana; O'Connor, David; Chen, Bosi et al. (2017) Enhancing studies of the connectome in autism using the autism brain imaging data exchange II. Sci Data 4:170010|
|Schoch, Kelly; Meng, Linyan; Szelinger, Szabolcs et al. (2017) A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay. Am J Hum Genet 100:343-351|
|Green, Shulamite A; Hernandez, Leanna; Bookheimer, Susan Y et al. (2017) Reduced modulation of thalamocortical connectivity during exposure to sensory stimuli in ASD. Autism Res 10:801-809|
|Dickinson, Abigail; DiStefano, Charlotte; Senturk, Damla et al. (2017) Peak alpha frequency is a neural marker of cognitive function across the autism spectrum. Eur J Neurosci :|
|Varcin, Kandice J; Jeste, Shafali S (2017) The emergence of autism spectrum disorder: insights gained from studies of brain and behaviour in high-risk infants. Curr Opin Psychiatry 30:85-91|
|DiStefano, Charlotte; Gulsrud, Amanda; Huberty, Scott et al. (2016) Identification of a distinct developmental and behavioral profile in children with Dup15q syndrome. J Neurodev Disord 8:19|
|Tsang, Tawny; Gillespie-Lynch, Kristen; Hutman, Ted (2016) Theory of Mind Indexes the Broader Autism Phenotype in Siblings of Children with Autism at School Age. Autism Res Treat 2016:6309189|
|Harrop, Clare; Gulsrud, Amanda; Shih, Wendy et al. (2016) Characterizing caregiver responses to restricted and repetitive behaviors in toddlers with autism spectrum disorder. Autism 20:330-42|
|Miller, Meghan; Iosif, Ana-Maria; Young, Gregory S et al. (2016) School-age outcomes of infants at risk for autism spectrum disorder. Autism Res 9:632-42|
|Gulsrud, Amanda C; Hellemann, Gerhard; Shire, Stephanie et al. (2016) Isolating active ingredients in a parent-mediated social communication intervention for toddlers with autism spectrum disorder. J Child Psychol Psychiatry 57:606-13|
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