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Genomic Influences on Developmental Course and Outcome in Infants at Risk of ASD: A BSRC Study

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There has been substantial progress in identifying ASD susceptibility genes; specifically, rare de novo and inherited ‘copy number variants’ (CNVs) involving neuronal synaptic genes. These rare variants appear to be highly penetrant, and collectively, account for a significant proportion of ASD cases. Concurrently, studies of younger siblings of children with ASD have helped inform the field about the earliest signs of autism, although behaviourally-based assessments are of uncertain stability when conducted at an early age. If genetic biomarkers could be used to identify infants likely to develop ASD, this could revolutionize opportunities for earlier diagnosis and treatment. Given the etiologic heterogeneity of ASD and the low frequency of individual CNVs, the success of such efforts will depend on collaboration to generate sufficiently large samples. The research team is ideally positioned to lead such efforts, based on 1) the largest collective sample of high-risk infants internationally; 2) extensive longitudinal phenotypic measures from age 6 to 36 months across sites; 3) ongoing collection of common measures compiled in a central database; 4) close relationships with participating families facilitating re-consenting for genetic studies; 5) links to large-scale sequencing efforts involving international ASD cohorts generating a comprehensive battery of candidate CNVs for microarray testing. The researchers will recruit a total of 435 families from among their current research participants to obtain DNA samples from high-risk infants, probands (i.e., the older child in the family with the established ASD diagnosis) and parents. Recruitment will be limited to families in which the high-risk infant has been followed to at least 3 years, to ensure reliability of diagnostic outcome assessment. A biorepository including DNA samples and cell lines from the BSRC families will be established within the Autism Genetic Resource Exchange (AGRE), housed at the NIMH Center for Genetic Studies at Rutgers University, and funded by a parallel grant submission to the Simons Foundation. The development of genomic risk assessment and testing strategies based on these discoveries has the potential to transform clinical practice, optimizing development, outcomes and quality of life for the many individuals and families affected by ASD.