Abstract
Aims/hypothesis
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/interpretation
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.
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References
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Acknowledgements
We would like to thank all of the attending diabetologists of the patients in the Czech Republic and Slovakia (particularly Lubomir Barak and Emilia Jancova from the Children Diabetes Centre, Bratislava, Slovakia; Beata Milosovicova from the Pediatric Endocrinology Outpatient Clinic, Bratislava, Slovakia). We are also grateful to Martina Balogova, Ivica Masindova, Dominika Balaziova and Alica Mitkova from the DIABGENE Laboratory (Institute of Experimental Endocrinology, Bratislava, Slovakia) and Klara Vesela and Petra Peldova (2nd Faculty of Medicine, Charles University in Prague, Czech Republic) for technical support.
Also, we would like to thank Sian Ellard and Kevin Colclough from the Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, UK for their contribution to the discussion.
Funding
This work was supported by research grants of the DIABGENE Laboratory (Transendogen/26240220051) which is supported by the Research & Development Operational Programme and funded by the European Regional Development Fund and Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic (2/0151/11). This study was also supported by grants from the Czech Ministry of Health (NT11402 and MH CZ–DRO, University Hospital Motol, Prague, the Czech Republic 00064203).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
Contribution statement
All authors contributed to the study design and reviewed the manuscript critically and approved the final version. JS and PD researched data and wrote the manuscript; OC wrote the manuscript; LD, DS, LV and MH researched data; and MS, MP, IK, JL, DG and SP reviewed/edited the manuscript.
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Juraj Stanik and Petra Dusatkova are joint first authors.
Daniela Gasperikova and Stepanka Pruhova are joint senior authors.
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Stanik, J., Dusatkova, P., Cinek, O. et al. De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed. Diabetologia 57, 480–484 (2014). https://doi.org/10.1007/s00125-013-3119-2
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DOI: https://doi.org/10.1007/s00125-013-3119-2