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

Thomas W. Laver; Kevin Colclough; Maggie Shepherd; Kashyap Patel; Jayne A. L. Houghton; Petra Dusatkova; Stepanka Pruhova; Andrew D. Morris; Colin N. Palmer; Mark I. McCarthy; Sian Ellard; Andrew Tt Hattersley; Michael N. Weedon

doi:10.2337/db16-0628

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

Thomas W. Laver, Kevin Colclough, Maggie Shepherd, Kashyap Patel, Jayne A. L. Houghton, Petra Dusatkova, Stepanka Pruhova, Andrew D. Morris, Colin N. Palmer, Mark I. McCarthy, Sian Ellard, Andrew Tt Hattersley, Michael N. Weedon (Lead / Corresponding author)

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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.

Original language	English
Pages (from-to)	3212-3217
Number of pages	6
Journal	Diabetes
Volume	65
Issue number	10
Early online date	2 Aug 2016
DOIs	https://doi.org/10.2337/db16-0628
Publication status	Published - Oct 2016

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10.2337/db16-0628

Author Accepted Manuscript
This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at [insert journal URL: http://diabetes.diabetesjournals.org.
Accepted author manuscript, 738 KB

The Scottish eHealth Informatics Research Centre (E-HIRCs) (Joint with Universities of Aberdeen, Glasgow, Edinburgh, Strathclyde, St Andrews & Leicester and ISD)
Colhoun, H. (Investigator), Donnan, P. (Investigator), Guthrie, B. (Investigator), Jefferson, E. (Investigator), MacDonald, T. (Investigator), McCowan, C. (Investigator), Morris, A. (Investigator), Pearson, E. (Investigator), Sullivan, F. (Investigator) & Swedlow, J. (Investigator)
Medical Research Council
1/03/13 → 31/12/18
Project: Research

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@article{d9efd18472af4071b51c49c73bb6d008,

title = "The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes",

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.",

author = "Laver, {Thomas W.} and Kevin Colclough and Maggie Shepherd and Kashyap Patel and Houghton, {Jayne A. L.} and Petra Dusatkova and Stepanka Pruhova and Morris, {Andrew D.} and Palmer, {Colin N.} and McCarthy, {Mark I.} and Sian Ellard and Hattersley, {Andrew Tt} and Weedon, {Michael N.}",

note = "Funding for this research was provided by: Royal Society (105636/Z/14/Z), Medical Research Council (MR/M005070/1), National Institute for Health Research, Wellcome Trust, Ministry of Health, Czech Republic (00064203/6001)",

year = "2016",

month = oct,

doi = "10.2337/db16-0628",

language = "English",

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pages = "3212--3217",

journal = "Diabetes",

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T1 - The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes

AU - Laver, Thomas W.

AU - Colclough, Kevin

AU - Shepherd, Maggie

AU - Patel, Kashyap

AU - Houghton, Jayne A. L.

AU - Dusatkova, Petra

AU - Pruhova, Stepanka

AU - Morris, Andrew D.

AU - Palmer, Colin N.

AU - McCarthy, Mark I.

AU - Ellard, Sian

AU - Hattersley, Andrew Tt

AU - Weedon, Michael N.

N1 - Funding for this research was provided by: Royal Society (105636/Z/14/Z), Medical Research Council (MR/M005070/1), National Institute for Health Research, Wellcome Trust, Ministry of Health, Czech Republic (00064203/6001)

PY - 2016/10

Y1 - 2016/10

N2 - 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.

AB - 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.

U2 - 10.2337/db16-0628

DO - 10.2337/db16-0628

M3 - Article

C2 - 27486234

SN - 0012-1797

VL - 65

SP - 3212

EP - 3217

JO - Diabetes

JF - Diabetes

IS - 10

ER -

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

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The Scottish eHealth Informatics Research Centre (E-HIRCs) (Joint with Universities of Aberdeen, Glasgow, Edinburgh, Strathclyde, St Andrews & Leicester and ISD)

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