Beyond Baby Siblings: Early Developmental Trajectories and Biomarkers of Risk for ASD

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PROJECT SUMMARY Identification of the earliest markers of risk for ASD holds tremendous clinical relevance, as it informs the implementation of early interventions that may attenuate symptoms and even prevent the development of ASD. Historically, infant siblings of children with ASD have constituted the primary focus of research in early markers. However, other high risk groups based on genetic diagnosis have been identified over the past several years. Studying infants at heightened genetic risk for ASD affords us a valuable opportunity to examine both distinct and shared neurobiological pathways to the core features that define autism symptoms. Such investigations not only shed light on mechanisms underlying atypical development in high-risk infants, but they can also clarify the ideal timing and target of early interventions that may modulate developmental trajectories. Here, we take a genetics-first approach and investigate biomarkers of risk for ASD and predictors of outcome in early infancy in three genetically defined groups with elevated risk: infants with an older sibling with ASD (familial risk), infants with Tuberous Sclerosis Complex (TSC), and infants with 22q11.2 deletion syndrome (22q11). We select these groups both because of our unique ability to study these populations at UCLA and because they allow us to examine ASD as it emerges in the context of three genetic pathways: polygenic risk (familial risk), single gene mutations (TSC), and copy number variation (22q11.2 deletion). We combine electrophysiology (EEG) with magnetic resonance imaging (MRI) to examine neurodevelopmental processes in the first year of life that may underlie the impairments that define ASD: (1) resting state/baseline neural synchrony and connectivity, (2) low level sensory processing and (3) brain activity and connectivity in language and salience networks. We study infants at 1.5, 3, 6, 9, 12 months with MRI (1.5 and 9 months), EEG (3-12 months), and behavioral (3-12 months) assays and then perform standardized assessments of cognition and autism symptoms at 12, 24 and 36 months. The project has synergy with the other ACE projects. Infants demonstrating early signs of ASD in this project will be referred to the infant intervention study in Project II (PI: Kasari). With Project III (PI: Dapretto), we share leadership and employ common measures of brain activity and connectivity. This project also will rely on the Diagnostic and Phenotyping Core (PI: McCracken, Co-PI Gulsrud) for developmental and diagnostic testing. We also will integrate with the Biomarkers Core (PI: Geschwind, Co-PI Jeste), with data collection performed in the Jeste and Dapretto labs and imaging/EEG data combined with data from the other projects for larger scale analyses of heterogeneity from infancy to adolescence. Saliva samples for genetics will be gathered at baseline from all participants for analysis of CNV's and polygenic risk. Each aim of this project is grounded in the overarching hypotheses that we will: (1) identify distinct behavioral and brain based trajectories and areas of convergence across these risk groups in early development and (2) quantify predictive markers of atypical development and ASD across groups before age 12 months. !