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    The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes.

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    URI
    http://hdl.handle.net/11287/618698
    Author
    Laver, T. W.
    Colclough, Kevin
    Shepherd, Maggie
    Patel, K.
    Houghton, Jayne A. L.
    Dusatkova, P.
    Pruhova, S.
    Morris, A. D.
    Palmer, C. N.
    McCarthy, M. I.
    Ellard, Sian
    Hattersley, Andrew T.
    Weedon, M. N.
    Date
    2016-08-02
    Journal
    Diabetes
    Type
    Journal Article
    Publisher
    American Diabetes Association
    DOI
    10.2337/db16-0628
    Rights
    Archived with thanks to Diabetes
    Metadata
    Show full item record
    Abstract
    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.
    Citation
    The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes. 2016 Oct;65(10):3212-7 Diabetes
    Publisher URL
    http://dx.doi.org/10.2337/db16-0628
    Collections
    • 2016 RD&E publications
    • Diabetes/Endocrine Services
    • Molecular Genetics

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