The conundrum in diagnosing Maturity-Onset Diabetes of the Young (MODY) in a large German pedigree with early-onset diabetes and a novel HNF1A variant

Genetic screening for maturity-onset diabetes of the young (MODY) involves sequencing of the coding regions of known disease-associated genes. We describe the complex and challenging diagnostic journey of a patient with early-onset diabetes with a novel, intronic HNF1A variant likely affecting a branching site. The patient was diagnosed with diabetes at the age of 10 years after incidental hyperglycemia (HbA1c 8.1%, C-peptide 3.0 μg/dl), without polyuria, polydipsia, or weight loss. Type 1 diabetes associated autoantibodies were negative, but the patient had a strong family history of early-onset diabetes (classified as type 1 or type 2 diabetes). Initial genetic testing for HNF4A, GCK, HNF1A, and HNF1B coding regions (including exon/intron boundaries ± 20 bp) and MLPA were negative. Sulfonylureas provided good glycemic control until age 16, when insulin was added. At age 18, an expanded targeted next-generation sequencing (NGS) panel for MODY was also negative. At age 24, whole-exome-sequencing via NGS and additional analysis was conducted, focusing on synonymous and intronic variants, and revealed a heterozygous HNF1A variant (c.327-28A > G;p.?) in the patient and four affected relatives. The variant co-segregated with diabetes, and was predicted to affect splicing via branching site disruption, suggesting pathogenicity. In summary, this case highlights the importance of a comprehensive diagnostic approach that combines clinical, biochemical, and extended genetic evaluation. When MODY is strongly suspected despite negative targeted testing, broader sequencing—including intronic and regulatory regions—should be pursued. Accurate variant interpretation remains essential to prevent misclassification and to optimize diagnosis, treatment, and understanding of the genetic complexity of monogenic diabetes.