There is ample evidence that rare genetic variants may contribute to a small subset of individuals presenting with Autism Spectrum Disorders (ASDs). The characterization of these unusual cases may provide important insights into pathophysiological mechanisms underlying disease. Our laboratory has leveraged the comprehensive phenotyping capabilities of the Yale Autism Research Group to focus on the discovery of rare variants contributing to developmental and social disability. Recently we have studied three unrelated patients with ASD and/or Mental Retardation (MR) and chromosomal abnormalities, all of who were found to have disruptions of genes in the Contactin (CNTN) or Contactin Association Protein (CNTNAP) families, including CNTN4, CNTNAP2 and CNTNAP4. These neuronal adhesion and recognition molecules are known to play key roles in axon pathfinding, fasciculation and neuronal-glial interactions. We have undertaken extensive re-sequencing efforts and, in our initial analysis of Contactin Associated Protein, we have identified a statistically significant increase in the burden of potentially damaging missense mutations among 218 cases and 449 controls regardless of whether we consider all non-synonymous variants or only those predicted by bioinformatics approaches to be deleterious to protein function. This data is particularly compelling in light of two additional findings: a rare recessive mutation in this gene found in association with seizures, developmental delay and autistic features in Amish families;and, unpublished data from collaborators at UCLA showing a common haplotype of CNTNAP2 associated with language delay in individuals with Autism. Based on our recent findings we now propose to: 1) replicate the mutation burden analysis in CNTNAP2 and perform a similar preliminary study in patients with developmental delay but not social disability;2) perform initial and, if warranted, replication studies of the other molecules disrupted by chromosomal abnormalities, Contactin 4 and Contactin Associated Protein 4 and 3) continue our gene discovery efforts using both conventional and array based cytogenetics on the well-characterized patients recruited under Projects 1-IV of this application focusing on the identification of rare, deleterious changes in chromosome structure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH081756-05
Application #
8376562
Study Section
Special Emphasis Panel (ZHD1-MRG-C)
Project Start
Project End
2014-03-31
Budget Start
2012-04-27
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$324,189
Indirect Cost
$128,305
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Macari, Suzanne L; Koller, Judah; Campbell, Daniel J et al. (2017) Temperamental markers in toddlers with autism spectrum disorder. J Child Psychol Psychiatry 58:819-828
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Shic, Frederick (2016) Eye Tracking as a Behavioral Biomarker for Psychiatric Conditions: The Road Ahead. J Am Acad Child Adolesc Psychiatry 55:267-8
Chawarska, Katarzyna; Chang, Joseph; Campbell, Daniel (2015) In Reply. J Am Acad Child Adolesc Psychiatry 54:958-9
Kim, So Hyun; Macari, Suzanne; Koller, Judah et al. (2015) Examining the phenotypic heterogeneity of early Autism Spectrum Disorder: subtypes and short-term outcomes. J Child Psychol Psychiatry :
Klintwall, Lars; Macari, Suzanne; Eikeseth, Svein et al. (2015) Interest level in 2-year-olds with autism spectrum disorder predicts rate of verbal, nonverbal, and adaptive skill acquisition. Autism 19:925-33
Campbell, Daniel J; Shic, Frederick; Macari, Suzanne et al. (2014) Gaze response to dyadic bids at 2 years related to outcomes at 3 years in autism spectrum disorders: a subtyping analysis. J Autism Dev Disord 44:431-42
Ventola, Pamela; Saulnier, Celine A; Steinberg, Elizabeth et al. (2014) Early-emerging social adaptive skills in toddlers with autism spectrum disorders: an item analysis. J Autism Dev Disord 44:283-93

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