Duplications of 7q11.23, deleted in Williams-Beuren Syndrome, have been implicated in autism spectrum disorders (ASDs). A 1.5 Mb duplication was identified in one girl with severe expressive language deficits and anxiety among 1,142 ASD individuals screened for this duplication. Family-based association studies of Tag-SNPs in three genes ("STX1A," "CYLN2" and "GTF2i") in two multiplex autism family cohorts revealed strong association of two "GTF2i" SNPs and their haplotype in Cohort 1 and the combined families. The risk alleles and haplotype were associated with severe problems in social interaction and excessive repetitive behaviors. Our findings suggest the "GTF2i" gene is important in the etiology of autism in individuals with this duplication and in non-duplication cases with severe social interaction problems and repetitive behaviors.