A Non-Coding Disease Modifier of Pancreatic Agenesis Identified by Genetic Correction in a Patient-Derived iPSC Line

GATA6 is a critical regulator of pancreatic development, with heterozygous mutations in this transcription factor being the most common cause of pancreatic agenesis. To study the variability in disease phenotype among individuals harboring these mutations, a patient-induced pluripotent stem cell model was used. Interestingly, GATA6 protein expression remained depressed in pancreatic progenitor cells even after correction of the coding mutation. Screening the regulatory regions of the GATA6 gene in these patient cells and 32 additional agenesis patients revealed a higher minor allele frequency of a SNP 3′ of the GATA6 coding sequence. Introduction of this minor allele SNP by genome editing confirmed its functionality in depressing GATA6 expression and the efficiency of pancreas differentiation. This work highlights a possible genetic modifier contributing to pancreatic agenesis and demonstrates the usefulness of using patient-induced pluripotent stem cells for targeted discovery and validation of non-coding gene variants affecting gene expression and disease penetrance. [Display omitted] •A disease-modifying SNP was discovered using a pancreas agenesis iPSC line•This non-coding SNP is enriched in patients with GATA6-induced pancreas agenesis•The A variant of SNP rs12953985 depresses GATA6 expression in pancreas precursors Kishore et al. describe using a patient iPSC line to discover and model the impact of a non-coding variant on disease penetrance. The minor allele variant of a SNP downstream of GATA6 was enriched in patients with pancreas agenesis and was shown to depress GATA6 expression in pancreas progenitors.