Mouse Model of 17q12 deletion shows defects in craniofacial, brain and kidney development, and in glucose homeostasis.

17q12 deletion (17q12Del) syndrome is a copy number variant (CNV) disorder associated with neurodevelopmental disorders (NDDs) and renal cysts and diabetes syndrome (RCAD). Using CRISPR/Cas9 genome-editing, we generated a mouse model of 17q12Del syndrome on both inbred (C57BL/6N) and outbred (CD-1) genetic backgrounds. On C57BL/6N, the 17q12Del mouse has severe head development defects, potentially mediated by haploinsufficiency of Lhx1, a gene within the interval that controls head development. Phenotypes include brain malformations, particularly disruption of the telencephalon, and craniofacial defects. On the CD-1 background, the 17q12Del mouse survives to adulthood and shows milder craniofacial and brain abnormalities. We report postnatal brain defects using automated MRI-based morphometry. In addition, we demonstrate renal and blood glucose abnormalities relevant to RCAD. On both genetic backgrounds, we found sex-specific presentations, with male 17q12Del mice exhibiting higher penetrance and more severe phenotypes. Results from these experiments pinpoint specific developmental defects and pathways that guide clinical studies and a mechanistic understanding of the human 17q12Del syndrome. This mouse mutant represents the first and only experimental model to date for the 17q12 CNV disorder.