O-12 A CASE OF DIABETES ASSOCIATED WITH A DE NOVO PAX4 MUTATION AND CONCURRENT SMAD6 GENE MUTATION
Authors: Karakilic Ersen , Tufan Ceren , Kose Canan Ceylan , Sedar Saygılı Emre , Talaibekova Sezim , Silan Fatma 
Published: January 2025

Abstract

Introduction
Monogenic diabetes constitutes approximately 1-5 % of all diabetes cases. While there is substantial information available about the more common MODY subtypes, the rarer subtypes remain much less understood. In this report, we present a rare case of diabetes with no family history, characterized by a pathogenic mutation in the PAX4 gene, which has been previously linked to MODY 9, along with a concurrent SMAD6 mutation.

Clinical Case
A 24-year-old male patient presented to our clinic for the management of diabetes mellitus. He was initially diagnosed with diabetes at the age of 17 and was initially managed with metformin alone. However, due to inadequate blood sugar control, basal insulin was later added to his treatment regimen. At his most recent visit, his treatment included a combination of sitagliptin+metformin (50/1000 mg, BID) and insulin glargine (16 units per day). His medical history revealed a childhood operation for congenital heart disease.
Physical examination revealed nasal speech, a syndromic facial appearance (with downward-pointing ears and a flattened nasal root), and a limitation of internal rotation in the forearms. His BMI was 27.8 kg/m², and he had maintained a stable weight since the time of diagnosis.
Laboratory evaluations revealed that anti-GAD was negative, with a C-peptide level of 0.6 ng/mL, HbA1c of 10.1%, and fasting blood glucose of 118 mg/dL. Kidney function tests and liver enzyme tests were within normal limits. Since diagnosis, HbA1c values have generally not been within the target range, fluctuating widely between 6.6% and 14%. The patient exhibited no microalbuminuria, no neuropathic findings, and no signs of retinopathy. Additionally, there was no family history of diabetes.
Given the patient’s atypical diabetes history and syndromic findings, genetic analysis was undertaken. Whole exome sequencing, performed using next-generation sequencing, identified a PAX4 (c.1013C&gt;T) mutation, which is potentially pathogenic (Figure 1 and Figure 2) and a homozygous pathogenic mutation in the SMAD6 gene. The patient’s diabetes history was attributed to the PAX4 gene mutation, which has been previously associated with MODY9, while the cardiac and extremity abnormalities were believed to be linked to the SMAD6 gene mutation. The 3D structures of the wild-type and mutant protein for PAX4 variant was predicted (Figure 2).

Conclusion
Diabetes cases resulting from PAX4 gene mutations are quite rare and often involve a form of diabetes that requires insulin. While most cases reported in the literature include a family history, there are instances, such as in our case, where a de novo mutation is identified. The presence of the SMAD6 gene mutation has contributed to the additional syndromic findings. Increasing the reporting of monogenic forms of diabetes, will enhance the recognition of diabetes-related genes and contribute to advances in understanding its etiopathogenesis.Figure 1-a:Visualization of the PAX4 c.1013C&gt;T;p.A338V variant region using VarSome Figure 1-b:3D structures of PAX4 created using Swiss-Model and visualized with Chimera. A) Presents the mutated protein (Purple) superimposed on the WT protein (Pink). (B) The amino acid substitution is shown, with the wild-type amino acid in pink and the mutant amino acid in purple