Introduction: Maturity Onset Diabetes of the Young (MODY) constitutes a genetically and clinically heterogeneous type of Monogenic Diabetes (MD), characterized by early onset of hyperglycemia, autosomal dominant inheritance and defect in β-cell insulin secretion. To date, 14 different MODY subtypes have been reported, each one with a distinct genetic etiology.
Materials and Methods: We designed a NGS TGP of seven MODY genes (GCK, HNF1A, HNF4A, HNF1B, INS, ABCC8 and KCNJ11) and screened 50 patients fulfilling MODY criteria. The patients, with no pathogenic variant, were tested by Multiplex Ligation-dependent Probe Amplification (MLPA) for CNVs. All detected pathogenic variants were verified by Sanger sequencing.
Results: Fifteen pathogenic heterozygous variants were detected in sixteen unrelated patients (diagnosis rate 32%) of which 14% were ABCC8, 8% GCK, 6% HNF1A, 2% HNF4A and 4% r HNF1B gene variants. One digenic case (GCK and ABCC8) was detected. Five variants were novel (GCK; p.Cys371X, HNF1A;p.Asn402Tyr, HNF4A;p.Glu285Lys and ABCC8;p.Met1514Thr and p.Ser1386Phe). Two de novo heterozygous deletions of the whole HNF1B gene were detected in two patients by MLPA, increasing the diagnosis rate of this work to 36%. The ABCC8 MODY patients (14%) presented with a wide spectrum of clinical and biochemical characteristics: fasting blood glucose ranging from 103 to 365mg/dl (5.7-20.3mmol/l), HbA1c 6.2% to 11.9% (44.3 - 107mmol/mol), age of onset of diabetes from 9yrs to 42 yrs, BMI from 17.2 kg/m2 to 27.7 kg/m2 and birth weight from 2800gr to 4100gr. Similar phenotypic heterogeneity has been described in the ABCC8 (MODY12) patients reported in the literature to date
Conclusions: The application of NGS methodology in MD diagnosis provide rapid results, is cost effective compared to Sanger sequencing and increases diagnostic accuracy. In this work MODY 12 represented 14% of the patients studied, although it is considered rare (<1%) in the literature. This finding can be attributed to the high throughput methodology of NGS, rendering sequencing the ABCC8 gene (39 exons) feasible compared to Sanger sequencing. The phenotypic characteristics of the patients carrying ABCC8 variants, exhibit genetic heterogeneity, ranging from a mild phenotype, similar to the mild GCK phenotype, to a more severe phenotype, similar to that of HNF1A and HNF4A defects. Molecular genetic diagnosis of the MODY subtype is of outmost importance for clinical diagnosis, disease progression prognosis and family counseling. Furthermore, it specifies pharmacologic treatment, since different MODY subtypes require different therapeutic approaches, constituting an example of personalized medicine.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology