title: Clinical characteristics and molecular genetic analysis of 22 patients with neonatal diabetes from the South-Eastern region of Turkey: predominance of non-KATP channel mutations.
abstract: BACKGROUND
  Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes and usually presents in the first 6 months of life. We aimed to describe the clinical characteristics and molecular genetics of a large Turkish cohort of NDM patients from a single centre and estimate an annual incidence rate of NDM in South-Eastern Anatolian region of Turkey.
  
  
  METHODS
  NDM patients presenting to Diyarbakir Children State Hospital between 2010 and 2013, and patients under follow-up with presumed type 1 diabetes mellitus, with onset before 6 months of age were recruited. Molecular genetic analysis was performed.
  
  
  RESULTS
  Twenty-two patients (59% males) were diagnosed with NDM (TNDM-5; PNDM-17). Molecular genetic analysis identified a mutation in 20 (95%) patients who had undergone a mutation analysis. In transient neonatal diabetes (TNDM) patients, the genetic cause included chromosome 6q24 abnormalities (n=3), ABCC8 (n=1) and homozygous INS (n=1). In permanent neonatal diabetes (PNDM) patients, homozygous GCK (n=6), EIF2AK3 (n=3), PTF1A (n=3), and INS (n=1) and heterozygous KCNJ11 (n=2) mutations were identified. Pancreatic exocrine dysfunction was observed in patients with mutations in the distal PTF1A enhancer. Both patients with a KCNJ11 mutation responded to oral sulphonylurea. A variable phenotype was associated with the homozygous c.-331C>A INS mutation, which was identified in both a PNDM and TNDM patient. The annual incidence of PNDM in South-East Anatolian region of Turkey was one in 48 000 live births.
  
  
  CONCLUSIONS
  Homozygous mutations in GCK, EIF2AK3 and the distal enhancer region of PTF1A were the commonest causes of NDM in our cohort. The high rate of detection of a mutation likely reflects the contribution of new genetic techniques (targeted next-generation sequencing) and increased consanguinity within our cohort.
authors.affiliation: Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK.
authors.forename: Huseyin
authors.initials: H
authors.lastname: Demirbilek
authors.affiliation: Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK.
authors.forename: Ved Bhushan
authors.initials: VB
authors.lastname: Arya
authors.affiliation: Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK.
authors.forename: Mehmet Nuri
authors.initials: MN
authors.lastname: Ozbek
authors.affiliation: Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK.
authors.forename: Jayne A L
authors.initials: JA
authors.lastname: Houghton
authors.affiliation: Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK.
authors.forename: Riza Taner
authors.initials: RT
authors.lastname: Baran
authors.affiliation: Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK.
authors.forename: Melek
authors.initials: M
authors.lastname: Akar
authors.affiliation: Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK.
authors.forename: Selahattin
authors.initials: S
authors.lastname: Tekes
authors.affiliation: Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK.
authors.forename: Heybet
authors.initials: H
authors.lastname: Tuzun
authors.affiliation: Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Mackay
authors.affiliation: Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.affiliation: Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.affiliation: Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK Khalid.Hussain@ucl.ac.uk.
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
mesh_terms: D002675:Child, Preschool; D003241:Consanguinity; D003920:Diabetes Mellitus / Q000235:genetics* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D004838:Epiphyses / Q000002:abnormalities; D005260:Female; D000081410:Germinal Center Kinases; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation / Q000235:genetics; D010009:Osteochondrodysplasias / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014421:Turkey; D019892:eIF-2 Kinase / Q000235:genetics
chemical_list: D000081410:Germinal Center Kinases; D014157:Transcription Factors; C062602:transcription factor PTF1; C460640:EIF2AK3 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase