The Penetrance Of Pancreas Agenesis Caused By Gata6 Mutations Is Modified By A Non-Coding Snp

GATA6 is a critical regulator of pancreas development, with heterozygous mutations in this transcription factor being the most common cause of pancreas agenesis. However, patients harboring GATA6 mutations exhibit variability in disease phenotypes. We have used a pancreatic agenesis patient-induced pluripotent stem cell model to study this disorder. We found that after correcting the coding mutation in a pancreas agenesis patient’s iPS cell line, GATA6 protein expression was comparable to other wild type stem cell lines at the definitive endoderm stage of development but still depressed in pancreatic progenitors. To investigate this finding, we screened the regulatory regions of the GATA6 gene and identified a SNP in a 3’ regulatory region of GATA6, with the patient carrying the minor allele variant. We tested the SNP in 32 further patients with pancreatic agenesis caused by GATA6 mutations and found that the frequency of the minor allele was enriched in the pancreatic agenesis cohort. The minor allele variant disrupted binding of the orphan nuclear receptor RORα and reduced GATA6 expression and efficiency of pancreas differentiation. Our work highlights a possible genetic modifier contributing to the pancreatic agenesis phenotype in patients with GATA6 mutations and shows the benefits of using pluripotent stem cells to study the effects of non-coding genetic variants in modifying disease penetrance.