The First Case of Digenic MODY Diabetes Involving Compound Heterozygosity of Three Variants in the PDX1 and HNF1B Genes

Abstract

ABSTRACT Objectives We report a rare case of digenic MODY. In 2016, at age 15, the patient was diagnosed with type 1 diabetes and began insulin therapy. After discrepancies in her glycaemic control were observed, an extensive differential diagnosis was conducted. In 2024, genetic testing confirmed monogenic diabetes, allowing for tailored treatment of the patient. Methods and Results The initial diagnosis was type 1 diabetes, later revised to MODY after Sanger screening. Genetic testing detected c.293C>T, p.Ala98Val in the HNF1A gene, which was initially misinterpreted as a variant causing Maturity Onset Diabetes of the Young (MODY), an autosomal dominant monogenic diabetes. Eventually, next‐generation sequencing (NGS) revealed three heterozygous variants in the MODY genes: HNF1B and PDX1. The HNF1B and PDX1 genes are transcription factors responsible for pancreas development and insulin gene transcription. Two variants located very close to each other in the PDX1 gene were identified: c.694G>A, p.Gly232Ser and c.697G>T, p.Glu233Ter. The first causes an amino acid change, while the latter leads to an early termination codon. The third variant, c.827_828insT, p.Gly277ArgfsTer17, was found in the HNF1B gene, resulting in a premature STOP codon and a truncated nonsense protein product. This is the first report of a patient with a double MODY variant resulting in early protein termination. Overall, the available evidence suggests that all variants may be pathogenic. The variants' severity and likely digenic nature matched the proband's diabetes presentation, which didn't respond to oral agents and required insulin. Neither parent nor brother, each with a detected variant in a single gene, has developed diabetes. However, renal cysts were discovered in the mother and brother, and the father was diagnosed with prediabetes. Conclusions This case highlights the severe presentation of likely digenic MODY, similar to type 1 diabetes. As NGS use increases, more patients like these are expected to be identified.