The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes.
Manuscript - The common p R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes - clean final version.docx (80.76Kb) Figure 1 Panel A.pdf (64.23Kb) Figure 1 Panel B.pdf (64.11Kb) Supplementary Figure 1 - p.R114W Pedigrees.docx (453.4Kb) Supplementary Table 1 - Type 2 Cases and Controls Clinical Characteristics.xlsx (9.274Kb) Supplementary Table 2 - Haplotype Analysis.xlsx (16.68Kb) Supplementary Table 3 - Type 2 Cases Versus Controls.xlsx (12.83Kb) Supplementary Table 4 - White European Subset Results for p.R114W and Other HNF4A.docx (17.19Kb) Supplementary Table 5 - in silico predictions.xlsx (9.104Kb)Show MoreShow Less
American Diabetes Association
HNF4A mutations cause increased birth weight, transient neonatal hypoglycaemia 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 lack of co-segregation 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=2x10(-21)) for diabetes in our MODY cohort compared to controls. p.R114W heterozygotes do not have the increased birth weight of patients with other HNF4A mutations (3476g vs. 4147g, 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 compared to 71% for other HNF4A mutations. We re-define p.R114W as a pathogenic mutation causing 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.
This work was supported by a Wellcome Trust Senior Investigator award to A.T.H. and S.E. A.T.H. is also supported by an NIHR Senior Investigator award. Additional support came from the University of Exeter and the NIHR Exeter Clinical Research Facility. M.N.W. is supported by MRC grant (MR/M005070/1). TWL is funded by the Wellcome Trust and the Royal Society (grant no. 105636/Z/14/Z). The genotyping was supported by the project for conceptual development of research organization 00064203/6001 (Ministry of Health, Czech Republic).
This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.
E-pub ahead of print - 2 Aug 2016
2016 Aug; db160628. http://dx.doi.org/10.2337/db16-0628