SAT079 A Novel Variant In The Carboxyl Ester Lipase (CEL) Gene Causing MODY

Abstract

Abstract Disclosure: C.R. Medavarapu: None. M. McNutt: None. Introduction: Maturity-onset diabetes of the young (MODY) is a group of autosomal dominantly inherited disorders of non-autoimmune diabetes mellitus. Here, we report a patient initially diagnosed with type 2 DM and later found to have carboxyl ester lipase (CEL)-MODY. Case: A 51 year-old female was diagnosed with DM at the age of 44 and initially categorized as having type 2 DM based on normal GAD-65 antibodies. The patient’s DM was well controlled on semaglutide. The patient, however, reported chronic diarrhea/steatorrhea and intermittent dull abdominal pain which was not associated with semaglutide. The patient continued to have GI symptoms despite stopping the semaglutide. Abdominal imaging was unremarkable with a normal-appearing pancreas. Interestingly, the patient's daughter had similar gastric inflammatory symptoms and multiple members of the family have early-onset DM. Due to this symptom complex and similar presentation in the family, an inflammatory pathologic syndrome was suspected. A monogenetic auto-inflammatory syndrome was also considered in differential and the whole exome was analyzed. Genetic testing identified a novel, likely pathogenic heterozygous variant in CEL(NM_001807.5): c.1875del. Pathogenic variants in CEL are associated with MODY, type VIII. Discussion: Single-base deletions in the CEL gene can cause exocrine and endocrine pancreatic dysfunction. Our patient presented with a novel c.1875del variant in CEL that has not been reported in the literature as causative of disease nor as a variant in the general population. This variant lies in the variable number of tandem repeats (VNTR)-containing exon 11 of CEL. Two other single nucleotide deletions in this exon were described in the original report of CEL-MODY. The c.1875del variant results in the deletion of one nucleotide at position c.1875 of the CEL gene, causing a frameshift in the protein reading frame. Loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay is expected. The c.1875del CEL variant is classified as likely pathogenic, and it correlated with our patient's clinical and biochemical findings. Typically, patients with CEL-MODY develop pancreatic exocrine dysfunction in early childhood and later develop DM in their 40s. A genetic diagnosis helps in determining the choice of treatment, managing associated complications, and the need for further genetic counseling for the family. Insulin is the most appropriate treatment in CEL-MODY; however, other anti-DM drugs can also be used as seen in our patient. The risk of DM complications from CEL-MODY is unknown but patients can develop pancreatic cysts and clinicians should watch for these complications. Our case highlights the need for high suspicion for possible CEL-MODY and considering genetic testing in the setting of coexistent endocrine and exocrine pancreatic insufficiency. Presentation: Saturday, June 17, 2023