title: The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study.
abstract: BACKGROUND
  Traditional genetic testing focusses on analysis of one or a few genes according to clinical features; this approach is changing as improved sequencing methods enable simultaneous analysis of several genes. Neonatal diabetes is the presenting feature of many discrete clinical phenotypes defined by different genetic causes. Genetic subtype defines treatment, with improved glycaemic control on sulfonylurea treatment for most patients with potassium channel mutations. We investigated the effect of early, comprehensive testing of all known genetic causes of neonatal diabetes.
  
  
  METHODS
  In this large, international, cohort study, we studied patients with neonatal diabetes diagnosed with diabetes before 6 months of age who were referred from 79 countries. We identified mutations by comprehensive genetic testing including Sanger sequencing, 6q24 methylation analysis, and targeted next-generation sequencing of all known neonatal diabetes genes.
  
  
  RESULTS
  Between January, 2000, and August, 2013, genetic testing was done in 1020 patients (571 boys, 449 girls). Mutations in the potassium channel genes were the most common cause (n=390) of neonatal diabetes, but were identified less frequently in consanguineous families (12% in consanguineous families vs 46% in non-consanguineous families; p<0·0001). Median duration of diabetes at the time of genetic testing decreased from more than 4 years before 2005 to less than 3 months after 2012. Earlier referral for genetic testing affected the clinical phenotype. In patients with genetically diagnosed Wolcott-Rallison syndrome, 23 (88%) of 26 patients tested within 3 months from diagnosis had isolated diabetes, compared with three (17%) of 18 patients referred later (>4 years; p<0·0001), in whom skeletal and liver involvement was common. Similarly, for patients with genetically diagnosed transient neonatal diabetes, the diabetes had remitted in only ten (10%) of 101 patients tested early (<3 months) compared with 60 (100%) of the 60 later referrals (p<0·0001).
  
  
  CONCLUSIONS
  Patients are now referred for genetic testing closer to their presentation with neonatal diabetes. Comprehensive testing of all causes identified causal mutations in more than 80% of cases. The genetic result predicts the best diabetes treatment and development of related features. This model represents a new framework for clinical care with genetic diagnosis preceding development of clinical features and guiding clinical management.
  
  
  BACKGROUND
  Wellcome Trust and Diabetes UK.
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: De Franco
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Jayne A L
authors.initials: JA
authors.lastname: Houghton
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Hana
authors.initials: H
authors.lastname: Lango Allen
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury Foundation Trust, Salisbury, UK; University Hospital Southampton NHS Trust, Southampton, UK; Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Deborah J G
authors.initials: DJ
authors.lastname: Mackay
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury Foundation Trust, Salisbury, UK; University Hospital Southampton NHS Trust, Southampton, UK.
authors.forename: I Karen
authors.initials: IK
authors.lastname: Temple
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK. Electronic address: A.T.Hattersley@exeter.ac.uk.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D003920:Diabetes Mellitus / Q000145:classification / Q000235:genetics*; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*