Genetic spectrum and treatment implications of maturity-onset diabetes of the young in the eastern Black Sea region of Türkiye: a combined adult and pediatric cohort of 296 patients with identification of rare and novel variants.

BACKGROUND: Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous group of monogenic diabetes subtypes that is frequently misdiagnosed as type 1 or type 2 diabetes, and accurate genetic diagnosis enables a precision-medicine treatment approach. Regional Turkish data are limited, and previous Turkish series have been pediatric only. We characterized the genetic spectrum and therapeutic consequences of next-generation sequencing (NGS)-based MODY testing in a combined adult-and-pediatric cohort from the eastern Black Sea region of Türkiye.

METHODS AND RESULTS: We retrospectively analyzed 296 consecutive patients with clinically suspected MODY referred between January 2022 and June 2025. A targeted NGS panel covering 14 MODY genes was applied, variants were classified per 2015 ACMG/AMP criteria, and treatment changes attributable to the genetic diagnosis were extracted from medical records. Pathogenic or likely pathogenic (P/LP) variants were identified in 43 of 296 patients (14.5%); diagnostic yield rose to 26.0% with variants of uncertain significance included. GCK-MODY accounted for 72.1% of P/LP findings, with a recurrent frameshift c.1256del p.(Phe419SerfsTer12) across nine apparently unrelated families consistent with a regional founder allele. Rare subtypes included MODY4 (PDX1), MODY6 (NEUROD1), MODY8 (CEL), MODY10 (INS), MODY12 (ABCC8) and MODY13 (KCNJ11). The genetic diagnosis directly modified pharmacological therapy in 14 patients, including insulin discontinuation in three KATP-channel MODY and one INS-MODY case.

CONCLUSIONS: NGS-based MODY testing yields actionable findings in approximately one in seven clinically selected patients in this region and supports inclusion of MODY testing in routine endocrinology practice.