A case of maturity‐onset diabetes of the young with a pathogenic <i>HNF1A</i> variant and a coexisting <i>NEUROD1</i> variant

AIMS/INTRODUCTION: Maturity-onset diabetes of the young (MODY) accounts for at least 1%-5% of diabetes cases and is usually caused by single gene variants. Accurate diagnosis of MODY is important for effective management, especially in young individuals who are lean and lack islet autoantibodies. Only a few MODY cases associated with multiple gene variants have been reported. We here describe a rare case of MODY with a pathogenic HNF1A variant and a coexisting NEUROD1 variant. MATERIALS AND METHODS: We conducted an extensive clinical analysis and explored the complex genetic architecture of the case in order to provide insight into the etiology of MODY. The candidate variants were identified by comprehensive whole-exome and Sanger sequencing, and their functional impact was assessed by analysis of their effects on the surface charge or structural stability of HNF1A and NEUROD1. RESULTS: The proband, a 21-year-old woman with early-onset diabetes, was found to harbor a pathogenic HNF1A p.Arg159Trp variant and a coexisting NEUROD1 p.Arg98Ser variant of uncertain significance. The NEUROD1 variant was also present in her mother and sister, both of whom manifested impaired glucose tolerance, but was absent in her father and brother. Structural analyses suggested that the HNF1A variant alters the surface charge of the protein, whereas the NEUROD1 variant may affect protein structural stability. CONCLUSION: We have identified an unusual case of MODY with a pathogenic HNF1A variant and a coexisting NEUROD1 variant of uncertain significance, and structural analyses suggested that the NEUROD1 variant may affect protein structure.