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- Title
The Common p.R114W HNF4A Mutation Causes a Distinct Clinical Subtype of Monogenic Diabetes.
- Authors
Laver, Thomas W.; Colclough, Kevin; Shepherd, Maggie; Patel, Kashyap; Houghton, Jayne A. L.; Dusatkova, Petra; Pruhova, Stepanka; Morris, Andrew D.; Palmer, Colin N.; McCarthy, Mark I.; Ellard, Sian; Hattersley, Andrew T.; Weedon, Michael N.
- Abstract
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.
- Subjects
TYPE 2 diabetes; HEPATOCYTE nuclear factors; SULFONYLUREAS; GENETIC carriers; PREGNANCY; MANAGEMENT; HYPOGLYCEMIC agents; BIRTH weight; CELL receptors; DISEASE susceptibility; GENETIC mutation; RESEARCH funding; BIOINFORMATICS; HAPLOTYPES; ODDS ratio; THERAPEUTICS
- Publication
Diabetes, 2016, Vol 65, Issue 10, p3212
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db16-0628