Background: MODY is an autosomal dominant inherited type of diabetes with significant genetic heterogeneity. To date, there are mutations in more than ten different genes that result in the MODY phenotype and new mutations causing MODY are still being found.
Objective and hypotheses: In this study, we aimed to perform a molecular analysis of pediatric MODY patients by next-generation sequencing which enables the simultaneous analysis of multiple genes in a single test and to assess genotypephenotype relationships.
Method: Patients who were aged between 0 and 18 years and diagnosed as having MODY in four different pediatric endocrinology clinics were enrolled in the study. Molecular analysis of GCK, HNF1A, HNF4A, HNF1B, IPF1, NEUROD1, KLF11, CEL, PAX4, INS and BLK genes were performed on genomic DNA using next-generation sequencing. A pathogenicity for novel mutations were assessed by bioinformatic prediction softwares programs and segregation analyses.
Results: Fourty-two children with a diagnosis of MODY (mean age; 10.3±4.2 years, 22 males) were enrolled in the study and mutations were identified in 15 cases (36%). GCK mutations were detected in eight cases, HNF1B mutation in two, and HNF1A, IPF1, PAX4, INS and BLK mutations in each of five. We identified six novel missense mutations we believe causing MODY three mutations in GCK (V338M, C252S and V86A), one mutation in HNF1A (C241X), one mutation in IPF1 (G55D) and one mutation in PAX4 (R182C).
Conclusion: The results of this study showed that i) genetic diagnosis could be made in 36% of patients, ii) six novel mutations were identified, and iii) it would be possible to establish novel mutations with further larger molecular studies given that the advantages of next-generation sequencing analysis with regard to cost and time.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology