484 Whole Genome Sequencing Analysis of Gastroparesis

Abstract

INTRODUCTION: Gastroparesis is a disorder characterized by delayed gastric emptying of solid food in the absence of mechanical obstruction of the stomach, resulting in the cardinal symptoms of early satiety, postprandial fullness, nausea, vomiting, belching and bloating. To ascertain the genetic risk factors for gastroparesis we conducted the first to date whole genome sequencing (WGS) study of gastroparesis cohort. METHODS: We investigated the frequency and effect of rare loss-of-function (LOF) variants in patients with idiopathic and diabetic gastroparesis enrolled in a clinical study, VLY686-2301. The dataset consisted of 119 WGS samples. RESULTS: Among rare LOF variants, we report an increased frequency of a frameshift mutation within Motilin Receptor (MLNR) gene, variant rs562138828. Motilin is a 22 amino acid peptide hormone expressed throughout the gastrointestinal (GI) tract. The protein encoded by this gene is a motilin receptor which is a member of the G-protein coupled receptor 1 family. We have shown an increased frequency of a frameshift mutation with MAF 0.01 as compared 0.0009 AF in GNOMAD (P-value = 0.01) with Odds Ratio of 21.9. We detect 4/119 gastroparesis patients carry the variant of interest that results in p.Leu202ArgfsTer105. Noteworthy is the fact that the 4 cases were equally split among idiopathic and diabetic, so this possible Gastroparesis risk factor appears to be agnostic as to condition. The finding may be of direct relevance to treatment as individuals with the identified mutation may respond differently to gastroparesis treatments especially those targeting MLNR. Among other rare LOF, we identified a case of CHD7 discussed in literature in gastro-related context and a case of CFTR duodenal stenosis pathogenic variant. The CFTR variant has been seen in pancreatitis and is likely causative of Cystic Fibrosis Gut which is characterized by increased mucous viscosity and development of intestinal inflammation, dysbiosis, and dysmotility. CONCLUSION: Whole genome sequencing of gastroparesis patient samples showed enrichment for rare variants in the MTLR in cases compared with controls. The identified LOF variants within the region can serve as a risk factor for disease as well as inform treatments, especially given the knowledge of different response to treatment.