Transcriptional consequences of 16p11.2 microdeletion/microduplication syndrome in mouse cortex converges on genes and pathways associated with autism and known intellectual disability syndromes. I. Blumenthal1, A. Ragavendran1, S. Erdin1, C. Golzio2, A. Sugathan1, J. Guide1, V. Wheeler1, A. Reymond3, N. Katsanis2, J. F. Gusella1,4,5, M. E. Talkowski1,4,5 1) Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA; 2) Center for Human Disease Modeling and Department of Cell biology, Duke University, Durham, NC; 3) Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland; 4) Broad Institute of MIT and Harvard, Cambridge, MA; 5) Department of Neurology, Harvard Medical School, Boston, MA.

   Reciprocal copy number variation (CNV) of a 593 kb region of 16p11.2 is a common genetic cause of autism spectrum disorder (ASD). However, it is not fully penetrant and confers risk across diverse phenotypic outcomes, including ASD, schizophrenia, obesity, and other neurological and anthropometric traits. To explore its molecular consequences, we performed RNA-sequencing in mouse models harboring CNV of the syntenic 7qf3 region. We initially sequenced the cerebral cortex of 16 mice (4 del, 4 dup, 8 control). Expression of all genes in the CNV region correlated with DNA copy number, with no evidence of dosage compensation. We observed positional effects in cis which were restricted to segments spanning a second genomic disorder locus: the distal 16p11.2 syndrome in human. Overall, 16p11.2 CNV was associated with altered expression of genes and networks that converge on multiple hypotheses of ASD pathogenesis, including synaptic function (e.g., NRXN1, NRXN3), chromatin modification (e.g., CHD8, EHMT1, MECP2), and transcriptional regulation (e.g.,TCF4, SATB2). Notably, we observed differential expression of genes involved in classic forms of intellectual disability (e.g., FMR1, CEP290, BBS12), and among OMIM phenotypes we find strong statistical enrichment for genes related to Joubert and Bardet-Biedl syndromes (p = 2.36e-4 and 0.046, respectively), as well as pathways related to ciliary development (p = 0.025). Collectively, these data show perturbation of genes and networks involved in ASD and a spectrum of phenotypes associated with intellectual disability. We also performed RNA-seq analyses in lymphoblastoid cell lines (LCL) of multiplex families from AGRE, and compared our results to microarray studies of 81 CNV cases and 17 controls (see Reymond et al. abstract). These LCL datasets show striking consistency between the specificity of the cis positional effects, as well as the association with Bardet-Biedl and Joubert syndromes (p = 0.026 and 0.047, respectively), as well as obesity related pathways. Given the consistency of these findings and the pleiotropic effects of 16p11.2 CNV, we have expanded these analyses to 48 mice and 6 tissues (cortex, cerebellum, striatum, white fat, brown fat, liver), and these analyses are in progress. Our results suggest that 16p11.2 CNVs disrupts expression networks that involve other genes and pathways known to contribute to ASD and intellectual disability, suggesting an overlap in mechanisms of pathogenesis.

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