The importance of combined NGS and MLPA genetic tests for differential diagnosis of maturity onset diabetes of the young

Jovana Komazec, Vera Zdravkovic, Silvija Sajic, Maja Jesic, Marina Andjelkovic, Sonja Pavlovic, Milena Ugrin

Maturity onset diabetes of the young (MODY) is a rare form of monogenic diabetes. Being clinically and genetically heterogeneous, it is often misdiagnosed as type 1 or type 2 diabetes, leading to inappropriate therapy. MODY is caused by a single gene mutation. Thirteen genes, defining 13 subtypes, have been identified to cause MODY. A correct diagnosis is important for the right therapy, prognosis and genetic counseling. Twenty nine unrelated pediatric patients clinically suspected to have MODY diabetes were analyzed using TruSight One panel for next generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) assay. In this study we identified variants in MODY genes in 22 out of 29 patients (75.9%). Using two genetic tests, NGS and MLPA, we detected both single nucleotide variants and large deletions in patients. Most of the patients harbored a variant in the GCK gene (11/22), followed by HNF1B (5/22). The rest of variants were found in the NEUROD1 and HNF1A genes. We identified one novel variant in the GCK gene: c.596T>C, p.Val199Ala. The applied genetic tests excluded the suspected diagnosis of MODY in two patients and reviled variants in other genes possibly associated with patient's clinical phenotype. In our group of MODY patients most variants were found in the GCK gene, followed by variants in HNF1B, NEUROD1 and HNF1A genes. The combined NGS and MLPA based genetic tests presented a comprehensive approach for analyzing patients with suspected MODY diabetes and provided a successful differential diagnosis of MODY subtypes.