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Replicated linear association between DUF1220 copy number and severity of social impairment in autism


Sequences encoding DUF1220 protein domains exhibit an exceptional human-specific increase in copy number and have been associated with several phenotypes related to brain size. Autism is a highly heritable and heterogeneous condition characterized behaviorally by social and communicative impairments, and increased repetitive and stereotyped behavior. Given the accelerated brain growth pattern observed in many individuals with autism, and the association between DUF1220 subtype CON1 copy number and brain size, we previously investigated associations between CON1 copy number and autism-related symptoms. We determined that CON1 copy number increase is associated with increasing severity of all three behavioral features of autism. The present study sought to replicate these findings in an independent population (N = 166). Our results demonstrate a replication of the linear relationship between CON1 copy number and the severity of social impairment in individuals with autism as measured by Autism Diagnostic Interview—Revised Social Diagnostic Score, such that with each additional copy of CON1 Social Diagnostic Score increased 0.24 points (SE = 0.11, p = 0.036). We also identified an analogous trend between CON1 copy number and Communicative Diagnostic Score, but did not replicate the relationship between CON1 copy number and Repetitive Behavior Diagnostic Score. Interestingly, these associations appear to be most pronounced in multiplex children. These results, representing the first replication of a gene dosage relationship with the severity of a primary symptom of autism, lend further support to the possibility that the same protein domain family implicated in the evolutionary expansion of the human brain may also be involved in autism severity.

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Funding for this work was provided by NIH grant R01 MH081203 (JMS), by SFARI Pilot Grant 309230 from the Simons Foundation for Autism Research (JMS), and by a Colorado Clinical and Translational Science Institute (CCTSI) Award TL1 TR001081 (VBSQ). We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. We also thank Nathan Anderson for excellent technical assistance.

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Correspondence to J. M. Sikela.

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J. M. Davis and V. B. Searles Quick contributed equally to this manuscript.

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Davis, J.M., Searles Quick, V.B. & Sikela, J.M. Replicated linear association between DUF1220 copy number and severity of social impairment in autism. Hum Genet 134, 569–575 (2015).

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  • Repetitive Behavior
  • Autism Diagnostic Observation Schedule
  • Vineland Adaptive Behavior Scales
  • DUF1220 Domain
  • Diagnostic Score