PHENOTYPIC AND GENOTYPIC ANALYSIS OF HEREDITARY PANCREATITIS IN PATIENTS AND POTENTIAL CANDIDATES FOR TOTAL PANCREATECTOMY WITH ISLET AUTOTRANSPLANTATION (TP-IAT)

Abstract

Introduction: Hereditary Pancreatitis (HP) is caused by inheritance of genetic mutations in PRSS1/2, SPINK1, CFTR and CTRC gene regions. HP frequently results in inflammation of the pancreas from a young age, chronic abdominal pain, dependency upon opioids, and elevated risk of pancreatic ductal adenocarcinoma (PDAC) at later stages of life. Total Pancreatectomy with Islet Autotransplantation (TP-IAT) effectively treats patients of HP and prevents diabetes and risk of pancreatic cancer later in life. This project aims to identify HP cases and assess the correlation between phenotypic disease outcome and genotypic mutation variant. Methods: Patients with HP were identified from hospital records and interviewed for phenotype. Criteria include: personal and family medical history, pain management, medical prescriptions, previous surgery, smoking and alcohol history, and quality of life. Salivary biosamples were obtained to be whole-exome-sequenced (WES). WES data was filtered using the VariantGrid pipeline with gnomAD pancreas-related disease frequency >1%. Results: 4 families of 42 individuals, plus 33 additional familial probands of HP had been identified thus far. All 4 families possess the mutation PRSS1, albeit different allelic variants (3 with R122H, 1 with A86T). One PRSS1 R122H mutation variant family also possessed SPINK1 N34S mutation, a known HP disease modifier mutation. In these well-phenotyped families, 23 PRSS1 and 5 SPINK1 genetic mutation carriers were identified from our study cohort. 13 of whom suffered from phenotypic symptoms of HP. Interestingly, 12 of the 33 probands have been genotyped and showed no known HP-associated mutation. Conclusion: Phenotypic disparity in mutation carriers suggests possible existence of unknown modifier genes for HP. Disease phenotype in probands with no known mutation also suggest possible existence of novel HP-associated mutations. Bioinformatics analysis studies of acquired WES data are currently underway for further investigation.