SAT-832 - MODY-6 Presenting with A Novel NEUROD1 Variant (Arg325Ser): Clinical Features and Artificial Intelligence-Assisted Bioinformatic Analysis

Background:
Maturity-onset diabetes of the young (MODY) is a diagnostic consideration in a patient presenting with hyperglycemia but lacking autoimmune markers. MODY-6, caused by NEUROD1 variants, remains underrecognized in clinical practice. We report a suspected MODY-6 case with a novel NEUROD1 variant.

Case:
A 20-year-old female was diagnosed with type 1 diabetes mellitus (T1DM) at age 7 after presenting with an infection and hyperglycemia (blood glucose 317 mg/dL, HbA1c 12.7%, bicarbonate 25.9 mmol/L, anion gap 17 mmol/L). Autoantibody panel was negative. She started insulin therapy and transitioned to a pump. Notably, she never developed diabetic ketoacidosis, and C-peptide levels remained low normal to minimally subnormal. Autoantibody panel remained negative for GAD-65, IA-2, and ZNT8. Her clinical course was notable for recurrent severe hypoglycemia. During adolescence, she was diagnosed with polycystic ovary syndrome and started metformin which reduced glucose variability. Her phenotype was striking for lifelong leanness (BMI 21). Family history was negative for diabetes. Genetic testing revealed a heterozygous variant (c.973 C>A, p.Arg325Ser) in NEUROD1. Although currently categorized as a variant of uncertain significance, the substitution affects a highly conserved residue in the transcriptional-activation and p300-binding domain of NEUROD1, a domain that is critical for β-cell development and function. These results suggested a diagnosis of MODY-6. The insulin pump was discontinued, and she is now managed with insulin degludec 8 units daily, metformin 500 mg daily, glipizide 5 mg daily, and insulin aspart as needed. Quality of life improved with better glycemic control and less hypoglycemia. Time-in-range is 78 - 85%. HbA1c is 6.8.

Discussion:
This case emphasizes that hyperglycemia should not be assumed to represent T1DM in the absence of autoantibodies. Serial antibody testing, phenotypic assessment, and timely genetic testing are essential when the clinical course is atypical. In this case a novel NEUROD1 variant was identified. The mutation resides within an 8-amino acid motif that is conserved in more than 120 mammalian species. The observed variant occurs rarely in population genome databases (variant frequency 0.000066, GnomAD_genomes). Artificial intelligence-assisted modeling suggests that the Arg325Ser variant interferes with complex formation between NEUROD1 and the transcription coactivator protein, p300. Recognition of NEUROD1-related MODY6, even without a family history, can prevent misclassification and allows individualized treatment. Our findings support the expansion of the genotype–phenotype spectrum for MODY-6 and highlight the importance of precision diagnostics in endocrinology. More work is required to fully understand the interaction between NEUROD1 and p300 and the impact of NEUROD1 variants on insulin regulation.

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