Heterozygous missense variant inGLI2impairs human endocrine pancreas development

SUMMARY Missense variants are the most common type of coding genetic variants. Their functional assessment is fundamental for defining any implication in human diseases and may also uncover genes that are essential for human organ development. Here, we applied CRISPR-Cas9 gene editing on human iPSCs to study a heterozygous missense variant in GLI2 identified in a paediatric hyperglycaemic patient and family members. GLI2 is a primary mediator of the Hedgehog pathway, which regulates pancreatic β-cell development in mice. However, neither mutations in GLI2 nor Hedgehog dysregulation have been reported as cause or predisposition to diabetes. A set of isogenic iPSC lines harbouring the missense variant were studied for their ability to differentiate into pancreatic β-like cells. Interestingly, iPSCs carrying the missense variant showed altered GLI2 transcriptional activity and impaired endocrine differentiation. Collectively, our findings underscore an essential role for GLI2 in human endocrine development and identify a novel variant that predisposes to diabetes.