J Pediatr Endocrinol Metab 2015; aop *Corresponding author: Sebahat Yılmaz Ağladıoğlu, MD, Pediatric Endocrinologist, Dr Sami Ulus Children’s Health and Disease Training and Research Hospital, Clinics of Pediatric Endocrinology, Ankara, Turkey, Phone: +90 312 305 65 15, Fax: +90 312 317 03 53, E-mail: sebahatyilmaz@yahoo.com Zehra Aycan: Pediatric Endocrinologist, Dr Sami Ulus Children’s Health and Disease Training and Research Hospital, Clinics of Pediatric Endocrinology, Yıldırım Beyazıt University, Ankara, Turkey Semra Çetinkaya, Veysel Nijat Baş, Aşan Önder and Havva Nur Peltek Kendirci: Pediatric Endocrinologist, Dr Sami Ulus Children’s Health and Disease Training and Research Hospital, Clinics of Pediatric Endocrinology, Ankara, Turkey Haldun Doğan and Serdar Ceylaner: Medical Genetics, Intergen Genetic Diagnosis and Reseach Center, Ankara, Turkey Sebahat Yılmaz Ağladıoğlu*, Zehra Aycan, Semra Çetinkaya, Veysel Nijat Baş, Aşan Önder, Havva Nur Peltek Kendirci, Haldun Doğan and Serdar Ceylaner Maturity onset diabetes of youth (MODY) in Turkish children: sequence analysis of 11 causative genes by next generation sequencing DOI 10.1515/jpem-2015-0039 Received January 24, 2015; accepted October 19, 2015 Abstract Background: Maturity-onset diabetes of the youth (MODY), is a genetically and clinically heterogeneous group of dis- easesand is often misdiagnosed as type 1 or type 2 diabe- tes. The aim of this study is to investigate both novel and proven mutations of 11 MODY genes in Turkish children by using targeted next generation sequencing. Methods: A panel of 11 MODY genes were screened in 43 children with MODY diagnosed by clinical criterias. Studies of index cases was done with MISEQ-ILLUMINA, and family screenings and confirmation studies of muta- tions was done by Sanger sequencing. Results: We identified 28 (65%) point mutations among 43 patients. Eighteen patients have GCK mutations, four have HNF1A, one has HNF4A, one has HNF1B, two have NEUROD1, one has PDX1 gene variations and one patient has both HNF1A and HNF4A heterozygote mutations. Conclusions: This is the first study including molecular studies of 11 MODY genes in Turkish children. GCK is the most frequent type of MODY in our study population. Very high frequency of novel mutations (42%) in our study population, supports that in heterogenous disorders like MODY sequence analysis provides rapid, cost effective and accurate genetic diagnosis. Keywords: children; maturity onset diabetes of youth (MODY); next generation sequencing. Introduction Maturity onset diabetes of the youth (MODY), which is a monogenic form of diabetes that is inherited in an auto- somal dominant manner, accounts for 1%–2% of all cases of diabetes, but it is often misdiagnosed as type 1 or type 2 diabetes. It encompasses a genetically and clinically het- erogeneous group of diseases affecting pancreatic β-cells and resulting in impaired insulin secretion [1]. Since 1992, mutations in 13 genes have been reported to cause MODY. The most prevalent mutations occur in the HNF1A, GCK and HNF4A genes [2]. The MODY subtypes differ in terms of the age of dia- betes onset, pattern of hyperglycemia, response to treat- ment, and associated extra pancreatic manifestations. Therefore, correct genetic diagnosis is important for lifelong treatment and patient prognosis [3]. Although genetic identification of MODY subtypes may have several benefits, a large number of patients have not been tested. The current guidelines related to genetic diagnosis rely on phenotype-guided screening of the most commonly implicated genes, but these guidelines do not provide comprehensive information for genetic testing or genetic counseling [4]. The current approach using Sanger sequencing is expensive, time consuming and establishes a genetic diagnosis among only a limited number of genes [5]. However, next-generation sequencing has great poten- tial for detecting all causative genes in monogenic diabetes [6, 7]. To our knowledge, this is the first study examin- ing of all of these genes using targeted next-generation sequencing in a Turkish population. The aim of this study was to detect both proven and novel gene mutations in Turkish children and to demonstrate genotype-phenotype correlations. Brought to you by | University of California Authenticated Download Date | 12/28/15 5:25 AM