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Diabetes. 2016 Oct;65(10):3212-7. doi: 10.2337/db16-0628. Epub 2016 Aug 2.

The Common p.R114W HNF4A Mutation Causes a Distinct Clinical Subtype of Monogenic Diabetes.

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Institute of Biomedical & Clinical Science, University of Exeter, Exeter, U.K.
Institute of Biomedical & Clinical Science, University of Exeter, Exeter, U.K. Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, U.K.
Department of Paediatrics, Second Faculty of Medicine, Charles University
and University Hospital Motol, Prague, Czech Republic.
Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K. Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K. National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
Institute of Biomedical & Clinical Science, University of Exeter, Exeter, U.K.


HNF4A mutations cause increased birth weight, transient neonatal hypoglycemia, and maturity onset diabetes of the young (MODY). The most frequently reported HNF4A mutation is p.R114W (previously p.R127W), but functional studies have shown inconsistent results; there is a lack of cosegregation in some pedigrees and an unexpectedly high frequency in public variant databases. We confirm that p.R114W is a pathogenic mutation with an odds ratio of 30.4 (95% CI 9.79-125, P = 2 × 10(-21)) for diabetes in our MODY cohort compared with control subjects. p.R114W heterozygotes did not have the increased birth weight of patients with other HNF4A mutations (3,476 g vs. 4,147 g, P = 0.0004), and fewer patients responded to sulfonylurea treatment (48% vs. 73%, P = 0.038). p.R114W has reduced penetrance; only 54% of heterozygotes developed diabetes by age 30 years compared with 71% for other HNF4A mutations. We redefine p.R114W as a pathogenic mutation that causes a distinct clinical subtype of HNF4A MODY with reduced penetrance, reduced sensitivity to sulfonylurea treatment, and no effect on birth weight. This has implications for diabetes treatment, management of pregnancy, and predictive testing of at-risk relatives. The increasing availability of large-scale sequence data is likely to reveal similar examples of rare, low-penetrance MODY mutations.

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