Novel variants of monogenic diabetes and impact of genetic diagnosis on treatment strategies

TL;DR

This paper shows that genetic testing for monogenic diabetes can lead to better treatment decisions, even in older patients who are often overlooked.

Contribution

The study highlights the importance of expanding genetic testing criteria for monogenic diabetes beyond young patients.

Findings

Genetic testing confirmed monogenic diabetes in 15.3% of patients tested.

Treatment changes based on genetic results occurred in 75% of eligible patients.

GCK gene variants were the most common cause of monogenic diabetes in both younger and older patients.

Abstract

Monogenic diabetes (MD) is a rare form of diabetes resulting from single-gene defects. While diagnostic guidelines are well established for young patients, individuals >25 years are frequently overlooked, despite the clinical value of molecular diagnosis for personalized therapy.

To evaluate genetic sequencing outcomes and their implications for treatment optimization in patients diagnosed with diabetes between 2017 and 2024 across all age groups.

Among 509 individuals tested for suspected MD, 78 (60.3% female) had a confirmed molecular diagnosis. Genetic testing was performed in patients with negative pancreatic autoantibodies, a family history of diabetes, or stable hyperglycemia without insulin requirement.

The median age at MD diagnosis was 18.3 (4–68.1) years, with a median diabetes duration of 4.5 (0–50) years. Forty-three patients (55.1%) were diagnosed before age 25 and thirty-five (45.6%) after 25 years. GCK variants predominated in both groups (81.4% and 74.3%, respectively), followed by HNF1A, HNF4A, and HNF1B. After molecular confirmation, 75% (18/24) of eligible patients underwent actionable treatment changes according to genotype, while six did not benefit from therapy adjustment.

These findings demonstrate a high diagnostic yield (15.3%) for MD and emphasize the need to broaden testing criteria to enable precise, gene-guided and on time treatment decisions.

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