title: De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed.
abstract: OBJECTIVE
  MODY is mainly characterised by an early onset of diabetes and a positive family history of diabetes with an autosomal dominant mode of inheritance. However, de novo mutations have been reported anecdotally. The aim of this study was to systematically revisit a large collection of MODY patients to determine the minimum prevalence of de novo mutations in the most prevalent MODY genes (i.e. GCK, HNF1A, HNF4A).
  
  
  METHODS
  Analysis of 922 patients from two national MODY centres (Slovakia and the Czech Republic) identified 150 probands (16%) who came from pedigrees that did not fulfil the criterion of two generations with diabetes but did fulfil the remaining criteria. The GCK, HNF1A and HNF4A genes were analysed by direct sequencing.
  
  
  RESULTS
  Mutations in GCK, HNF1A or HNF4A genes were detected in 58 of 150 individuals. Parents of 28 probands were unavailable for further analysis, and in 19 probands the mutation was inherited from an asymptomatic parent. In 11 probands the mutations arose de novo.
  
  
  CONCLUSIONS
  In our cohort of MODY patients from two national centres the de novo mutations in GCK, HNF1A and HNF4A were present in 7.3% of the 150 families without a history of diabetes and 1.2% of all of the referrals for MODY testing. This is the largest collection of de novo MODY mutations to date, and our findings indicate a much higher frequency of de novo mutations than previously assumed. Therefore, genetic testing of MODY could be considered for carefully selected individuals without a family history of diabetes.
authors: DIABGENE Laboratory, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, SK-833 06, Bratislava, Slovakia.
authors: Juraj
authors: J
authors: Stanik
authors: Petra
authors: P
authors: Dusatkova
authors: Ondrej
authors: O
authors: Cinek
authors: Lucia
authors: L
authors: Valentinova
authors: Miroslava
authors: M
authors: Huckova
authors: Martina
authors: M
authors: Skopkova
authors: Lenka
authors: L
authors: Dusatkova
authors: Daniela
authors: D
authors: Stanikova
authors: Mikulas
authors: M
authors: Pura
authors: Iwar
authors: I
authors: Klimes
authors: Jan
authors: J
authors: Lebl
authors: Daniela
authors: D
authors: Gasperikova
authors: Stepanka
authors: S
authors: Pruhova
mesh_terms: D018153:Czech Republic / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D000081410:Germinal Center Kinases; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010375:Pedigree; D015995:Prevalence; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D018154:Slovakia / Q000453:epidemiology
chemical_list: D000081410:Germinal Center Kinases; C496487:HNF1A protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D017346:Protein Serine-Threonine Kinases