6429 An Unusual Gene Mutation and Clinical Manifestation of MODY 10
Authors: Ambalavanan Jayachidambaram , Abdulhussein Osamah , Ferri-Guerra Juliana , Loria Gloriana Madrigal , Alkwatli Kenda , Iqbal Anira , Correa Ricardo Rafael 
Published: October 2024

Disclosure: J. Ambalavanan: None. O. Abdulhussein: None. J. Ferri-Guerra: None. G. Madrigal Loria: None. K. Alkwatli: None. A. Iqbal: None. R.R. Correa: None.

Introduction: Maturity-Onset Diabetes of the Young (MODY) is a rare monogenic form of diabetes characterized by impaired beta cell function accounting for &lt; 5% of all people with diabetes. About 14 different subtypes of MODY have been described in the. MODY 10 is an extremely rare form with mutation in the INS (insulin) gene. We present a previously unreported genetic mutation in the INS gene, its clinical course and subsequent management. Case: A 23-year-old female presented to us for consultation regarding new diagnosis of diabetes. She came to medical attention for pre-diabetes at the age of 16 years and was managed with diet control. She was officially diagnosed with diabetes by PCP in October 2022 after onset of polyuria and nocturia, and HbA1c of 8.7%. During initial evaluation, we suspected type 1 diabetes due to her age, low BMI of 17.61 kg/m2 and prescribed a CGM while we awaited extensive antibody evaluation. Within a week she reported average blood sugars in the 200-300 mg/dl range. As a result, she was on insulin glargine 5 units at bedtime. Within 3 months, her HbA1c dropped to 6.5% but she started experiencing frequent symptomatic hypoglycemia at work. At this point we suspected MODY due to age at diagnosis; antibody negative status for GAD-65, IA-2, ZnT8 and insulin; detectable C-peptide 1.7 ng/ml (0.81-3.85); low BMI and good glycemic control and frequent hypoglycemia on insulin. On evaluation of family history, she had a history of diabetes in maternal grandmother, paternal grandfather and paternal great uncle. Her parents did not have diabetes. We stopped glargine and started glipizide XL 2.5mg once daily. She was also referred to our clinical genetics team. On genetic evaluation she was found to have one heterozygous variant of uncertain significance in the INS gene. On further evaluation, this was found to be guanine to adenine substitution at c:139 in exon 2 of the INS gene on chromosome 11:2182063 resulting in a variant protein p.Gly47Ser which is a missense change that occurs when glycine (Gly) is replaced by serine (Ser) at position 47. This mutation has not been previously reported to be pathogenic or benign and has not been reported in significant frequency anywhere based on our literature search. Furthermore, in silico analysis supported that this missense variant had a deleterious effect on the insulin structure/function. Given the rarity of this condition, there are no formal guidelines or consensus regarding the management. During a subsequent follow up visit, we discussed that she fit the diagnosis clinically and suggested possible medications. In the end, we decided to change her from glipizide to sitagliptin 50mg daily as she was continuing to have lows at work. This helped avoid hypoglycemia and maintained time in rage at 98%. Conclusion: We present a patient with rare form of MODY 10 with a new mutation in c139:G&gt;A at exon 2 of INS gene managed with sulfonylurea and eventually DPP4 inhibitor.

Presentation: 6/2/2024