Next generation sequencing targeted gene panel in Greek MODY patients increases diagnostic accuracy

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• Maturity Onset Diabetes of the Young (MODY) is a genetically diverse monogenic diabetes.
• It presents with early onset, autosomal dominant inheritance, and impaired pancreatic beta-cell insulin secretion.
• Distinct genetic etiologies underlie various MODY subtypes.

Purpose of the Study:

• To identify molecular defects in 50 MODY patients using next-generation sequencing (NGS).
• To enhance diagnostic yield for monogenic diabetes subtypes.

Main Methods:

• A targeted gene panel of seven MODY genes was used for NGS screening.
• Multiplex ligation-dependent probe amplification (MLPA) was employed to detect copy number variations (CNVs).

Main Results:

• Pathogenic or likely pathogenic variants were found in 16% of patients.
• Five novel pathogenic variants were identified in GCK, HNF1A, HNF4A, and ABCC8 genes.
• Two de novo deletions of the HNF1B gene increased the diagnostic rate to 20%.

Conclusions:

• NGS offers rapid, accurate, and cost-effective genetic diagnosis for MODY.
• Accurate genetic subtyping is crucial for tailored treatment, prognosis, and genetic counseling.
• Despite advancements, some MODY cases remain undiagnosed, necessitating further research.