Two rare monogenic diabetes cases due to CEL mutations: one with MODY 8 phenotype, one presenting as type 1 diabetes

Ceren Tufan; Ersen Karakilic; Kose Canan Ceylan; Saygili Emre Sedar; Hayri Bostan; Fatma Sılan

doi:10.1530/endoabs.110.EP361

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Endocrine Abstracts (2025) 110 EP361 | DOI: 10.1530/endoabs.110.EP361

ECEESPE2025 ePoster Presentations Diabetes and Insulin (245 abstracts)

Two rare monogenic diabetes cases due to CEL mutations: one with MODY 8 phenotype, one presenting as type 1 diabetes

Ceren Tufan ¹ , Ersen Karakilic ¹ , Canan Ceylan Köse ¹ , Emre Sedar Saygili ¹ , Hayri Bostan ² & Fatma Sılan ¹

Author affiliations

¹Canakkale Onsekiz Mart University Faculty of Medicine, Endocrinology and Metabolism, Canakkale, Türkiye; ²Canakkale Mehmet Akif Ersoy State Hospital, Endocrinology and Metabolism, Çanakkale, Türkiye

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Introduction: Monogenic diabetes accounts for approximately 1-5% of all diabetes cases. Carboxyl-Ester Lipase(CEL) gene mutation-associated diabetes is extremely rare, accounting for less than 1% of all monogenetic diabetes. It is usually associated with MODY-8 but can cause different clinical presentations. CEL mutations can lead to islet cell loss due to defective protein accumulation in the pancreas. While insulin deficiency is expected, the coexistence of T1DM with autoimmune markers is notable. Case 1:A 52-year-old male with a 15-year history of diabetes mellitus(DM) and 13 years on insulin therapy presented for blood glucose regulation. His BMI was 23 kg/m², and his physical examination was unremarkable. He was on insulin glargine (28 U, OD), insulin aspart (14 U, TID), vildagliptin/metformin (BID), and dapagliflozin(OD). HbA1c was 8.7%, C-peptide 0.77 ng/mL, and Anti-GAD was negative. Other laboratory tests, including hemogram, renal function, and liver function tests, were within normal limits, with no albuminuria. Non-proliferative diabetic retinopathy was detected. His father and six siblings had been diagnosed with DM at a young age. Genetic analysis revealed a heterozygous CEL(c.1966G>C, p.A656P) mutation(Table 1). Case 2:A 28-year-old female with T1DM since age two presented for follow-up. Her BMI was 22 kg/m², and her physical examination was normal. She was on insulin aspart/degludec(30 U, BID) and insulin aspart(8 U, OD). HbA1c was 9.4%, C-peptide<0.1 ng/mL, and Anti-GAD was elevated(47.5 U/mL), while other diabetes-related autoantibodies were negative. Renal and liver function tests were normal, and the albumin-to-creatinine ratio was 76 mg/day, leading to ramipril(2.5 mg, OD) initiation. No diabetic retinopathy was found. She had no family history of DM. Genetic analysis identified a homozygous frameshift mutation in CEL (c.1876_2039del, p.V626fs*6). The 3D structures of wild-type and mutant proteins were predicted using SWISS-MODEL(Table 2).

Table 1: In silico analysis results of CEL c.1966G>C;p.A656P variant
Varyant	MutationTester	SIFT	SIFT Score	PANTHER	AlphaMissense	FATHMM
CEL, c.1966G>C;p.A656P (NM_001807.6)	Benign	Uncertain	0.01	Probably Benign Pdel:0.19	likely_benign Pathogenic score: 0.069	Benign Score:0.02312

Table 2 3D structures of CEL created using Swiss-Model and visualized with Chimera
	3D structures of CEL
Case 1CEL c.1966G>C;p.A656P (NM_001807.6)
Case 2CEL (c.1876_2039del, p.V626fs*6).

Conclusion: Cases of diabetes associated with CEL gene mutations are extremely rare and typically present as a form of diabetes requiring insulin therapy. While these mutations can lead to monogenic diabetes cases associated with MODY-8, their potential association with T1DM, as observed in our second case, suggests a broader clinical spectrum. Increased reporting of monogenic diabetes forms will enhance the recognition of diabetes-associated genes and contribute to a better understanding of its etiopathogenesis.