Genome-wide molecular effects of the neuropsychiatric 16p11 CNVs in an iPSC-iN neuronal model

Copy number variants (CNVs), either deletions or duplications, at the 16p11.2 locus in the human genome are known to increase the risk for autism spectrum disorders (ASD), schizophrenia, and for several other developmental conditions. Here, we investigate the global effects on gene expression and DNA methylation using a 16p11.2 CNV patient-derived induced pluripotent stem cell (iPSC) to induced neuron (iN) cell model system. This approach revealed genome-wide alterations to both gene expression and to DNA methylation patterns and also yielded specific leads on genes potentially contributing to some of the known 16p11.2 patient phenotypes. Specifically, PCSK9 is identified as a possible contributing factor in the development of facial abnormalities, as well as the reciprocal head circumference and body mass index (BMI) phenotypes seen in the deletion and duplication patients. Additionally, the protocadherin (PCDH) gene family is found to have significantly altered methylation patterns in the CNV patient samples. Investigated tissue specific gene expression patterns in induced neurons derived from induced pluripotent stem cells (iPSCs) from patients with 16p11.2 deletion and duplication.