title: Reclassification of diabetes etiology in a family with multiple diabetes phenotypes.
abstract: BACKGROUND
  Maturity-onset diabetes of the young (MODY) is uncommon; however, accurate diagnosis facilitates personalized management and informs prognosis in probands and relatives.
  
  
  OBJECTIVE
  The objective of the study was to highlight that the appropriate use of genetic and nongenetic investigations leads to the correct classification of diabetes etiology.
  
  
  METHODS
  A 30-year-old European female was diagnosed with insulin-treated gestational diabetes. She discontinued insulin after delivery; however, her fasting hyperglycemia persisted. β-Cell antibodies were negative and C-peptide was 0.79 nmol/L. Glucokinase (GCK)-MODY was suspected and confirmed by the identification of a GCK mutation (p.T206M).
  
  
  METHODS
  Systematic clinical and biochemical characterization and GCK mutational analysis were implemented to determine the diabetes etiology in five relatives. Functional characterization of GCK mutations was performed.
  
  
  RESULTS
  Identification of the p.T206M mutation in the proband's sister confirmed a diagnosis of GCK-MODY. Her daughter was diagnosed at 16 weeks with permanent neonatal diabetes (PNDM). Mutation analysis identified two GCK mutations that were inherited in trans-p. [(R43P);(T206M)], confirming a diagnosis of GCK-PNDM. Both mutations were shown to be kinetically inactivating. The proband's mother, other sister, and daughter all had a clinical diagnosis of type 1 diabetes, confirmed by undetectable C-peptide levels and β-cell antibody positivity. GCK mutations were not detected.
  
  
  CONCLUSIONS
  Two previously misclassified family members were shown to have GCK-MODY, whereas another was shown to have GCK-PNDM. A diagnosis of type 1 diabetes was confirmed in three relatives. This family exemplifies the importance of careful phenotyping and systematic evaluation of relatives after discovering monogenic diabetes in an individual.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism (F.K.K., A.R., G.T., A.B., A.L.W., A.L.G., K.R.O.), University of Oxford, Oxford OX3 7LE, United Kingdom; Oxford National Institute for Health Research Biomedical Centre (F.K.K., G.T., A.L.G., K.R.O.), Churchill Hospital, Oxford OX3 7LJ, United Kingdom; Department of Clinical Genetics (D.S.), Oxford University Hospitals National Health Service Trust, Oxford OX3 9DU, United Kingdom; Department of Pediatrics (N.P.M.), Royal Berkshire National Health Service Foundation Trust, Reading RG1 5AN, United Kingdom; and Institute of Biomedical and Clinical Science (S.E.), University of Exeter Medical School, Exeter EX4 4PY, United Kingdom.
authors.forename: Fotini K
authors.initials: FK
authors.lastname: Kavvoura
authors.forename: Anne
authors.initials: A
authors.lastname: Raimondo
authors.forename: Gayathiry
authors.initials: G
authors.lastname: Thanabalasingham
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Webster
authors.forename: Debbie
authors.initials: D
authors.lastname: Shears
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Mann
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Owen
mesh_terms: D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000145:classification* / Q000209:etiology* / Q000235:genetics; D016640:Diabetes, Gestational / Q000175:diagnosis*; D005260:Female; D006801:Humans; D010375:Pedigree; D011247:Pregnancy; D011644:Puerperal Disorders / Q000175:diagnosis*