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

2.50
Hdl Handle:
http://hdl.handle.net/11287/618698
Title:
The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes.
Authors:
Laver, T. W.; Colclough, Kevin; Shepherd, Maggie ( 0000-0003-2660-0955 ) ; Patel, K.; Houghton, Jayne A. L.; Dusatkova, P.; Pruhova, S.; Morris, A. D.; Palmer, C. N.; McCarthy, M. I.; Ellard, Sian ( 0000-0002-7620-5526 ) ; Hattersley, Andrew T.; Weedon, M. N.
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:
American Diabetes Association
Journal:
Diabetes
Issue Date:
2-Aug-2016
URI:
http://hdl.handle.net/11287/618698
DOI:
10.2337/db16-0628
PubMed ID:
27486234
Additional Links:
http://dx.doi.org/10.2337/db16-0628
Type:
Journal Article
Language:
en
ISSN:
1939-327X
Appears in Collections:
Diabetes/Endocrine Services; Molecular Genetics; 2016 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorLaver, T. W.en
dc.contributor.authorColclough, Kevinen
dc.contributor.authorShepherd, Maggieen
dc.contributor.authorPatel, K.en
dc.contributor.authorHoughton, Jayne A. L.en
dc.contributor.authorDusatkova, P.en
dc.contributor.authorPruhova, S.en
dc.contributor.authorMorris, A. D.en
dc.contributor.authorPalmer, C. N.en
dc.contributor.authorMcCarthy, M. I.en
dc.contributor.authorEllard, Sianen
dc.contributor.authorHattersley, Andrew T.en
dc.contributor.authorWeedon, M. N.en
dc.date.accessioned2016-08-23T15:36:40Z-
dc.date.available2016-08-23T15:36:40Z-
dc.date.issued2016-08-02-
dc.identifier.citationThe common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes. 2016 Oct;65(10):3212-7 Diabetesen
dc.identifier.issn1939-327X-
dc.identifier.pmid27486234-
dc.identifier.doi10.2337/db16-0628-
dc.identifier.urihttp://hdl.handle.net/11287/618698-
dc.description.abstractHNF4A 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.en
dc.languageENG-
dc.language.isoenen
dc.publisherAmerican Diabetes Associationen
dc.relation.urlhttp://dx.doi.org/10.2337/db16-0628en
dc.rightsArchived with thanks to Diabetesen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.subjectWessex Classification Subject Headings::Endocrinology::Diabetesen
dc.titleThe common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes.en
dc.typeJournal Articleen
dc.identifier.journalDiabetesen
dc.type.versionIn press (epub ahead of print)en
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