Monogenic diabetes characteristics in a transnational multicenter study from Mediterranean countries

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• Monogenic diabetes diagnosis impacts treatment and healthcare costs.
• Prevalence is understudied in South Europe, North Africa, and the Middle East, where diabetes in young adults is rising.
• Non-autoimmune diabetes in young adults is a growing concern in Mediterranean regions.

Purpose of the Study:

• To identify monogenic diabetes cases in young adults from Mediterranean countries.
• To analyze country-specific variations in monogenic diabetes diagnosis.
• To assess the clinical and genetic spectrum of early-onset diabetes in the region.

Main Methods:

• A transnational, multicenter study involving exome sequencing of 204 unrelated patients with diabetes.
• Evaluation of rare coding variants in 35 targeted genes for pathogenicity.
• Statistical analysis using ANOVA, chi-squared test, and factor analysis of mixed data.

Main Results:

• A genetic diagnosis rate of 17.6% was achieved, identifying 40 pathogenic or likely pathogenic variants (14 novel) in 36 patients.
• GCK, HNF1A, ABCC8, and HNF4A variants were the most common causes.
• Diagnosis rates varied significantly between countries, correlating with genetic ancestry. Carriers often presented with lower BMI and HbA1c, and less frequent insulin use.
• Genetic diagnoses led to treatment modifications in several patients.

Conclusions:

• The study reveals a diverse clinical and genetic landscape of diabetes in Mediterranean populations.
• Widespread genetic testing is crucial for the personalized management of early-onset diabetes.
• Findings underscore the need for tailored diagnostic approaches considering genetic ancestry.