The Clinical and Diagnostic Characterization of 6q24-Related Transient Neonatal Diabetes Mellitus: A Polish Pediatric Cohort Study

<b>Background/Objectives:</b> Transient neonatal diabetes mellitus (TNDM) is a form of neonatal diabetes mellitus (NDM) arising in the first weeks of life and remitting in infancy. Epigenetic aberrations at the imprinted 6q24 locus (overexpression of <i>PLAGL1</i>/<i>HYMAI</i>) are the most common causes of TNDM. The aim of this study was a retrospective clinical and genetic analysis of a Polish pediatric cohort, emphasizing the role of methylation-specific MLPA (MS-MLPA) in the diagnosis of TNDM. <b>Methods:</b> We conducted a retrospective analysis of the medical records of 22 patients with diabetes diagnosed at 1 year of age. The molecular studies included an analysis of the NDM gene panel by a targeted NGS and MS-MLPA for the 6q24 imprinting region. <b>Results:</b> 6q24-TNDM was confirmed in five patients, with a median age of diabetes remission of 4 months (IQR: 3-6 months). The MS-MLPA identified paternal UPD6 or isolated maternal hypomethylation of <i>PLAGL1</i> in three patients, and two had a paternal 6q24 duplication. <b>Conclusions:</b> In our group, changes in the 6q24 region were confirmed in 22.7% of NDM patients, indicating the usefulness of the MS-MLPA technique in the diagnosis and detection of imprinting defects. We acknowledge key limitations, including diagnostic delays and incomplete parental testing, which precluded trio-based confirmation of paternal UPD6 versus epimutation in some cases; future diagnostic workflows should incorporate an early trio-based SNP array or STR confirmation. A methylation analysis should be included early in the NDM genetic diagnosis process to provide genetic counseling and monitor patients for diabetes recurrence.