The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes
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 som...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Diabetes Association
2016
|
| _version_ | 1797094544711352320 |
|---|---|
| author | Laver, T Colclough, K Shepherd, M Patel, K Houghton, J Dusatkova, P Pruhova, S Morris, A Palmer, C McCarthy, M Ellard, S Hattersley, A Weedon, M |
| author_facet | Laver, T Colclough, K Shepherd, M Patel, K Houghton, J Dusatkova, P Pruhova, S Morris, A Palmer, C McCarthy, M Ellard, S Hattersley, A Weedon, M |
| author_sort | Laver, T |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T04:15:29Z |
| format | Journal article |
| id | oxford-uuid:c943c4e1-6db3-413c-99d6-73b3e83d73bd |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:15:29Z |
| publishDate | 2016 |
| publisher | American Diabetes Association |
| record_format | dspace |
| spelling | oxford-uuid:c943c4e1-6db3-413c-99d6-73b3e83d73bd2022-03-27T06:57:54ZThe common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:c943c4e1-6db3-413c-99d6-73b3e83d73bdEnglishSymplectic Elements at OxfordAmerican Diabetes Association2016Laver, TColclough, KShepherd, MPatel, KHoughton, JDusatkova, PPruhova, SMorris, APalmer, CMcCarthy, MEllard, SHattersley, AWeedon, MHNF4A 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. |
| spellingShingle | Laver, T Colclough, K Shepherd, M Patel, K Houghton, J Dusatkova, P Pruhova, S Morris, A Palmer, C McCarthy, M Ellard, S Hattersley, A Weedon, M The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes |
| title | The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes |
| title_full | The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes |
| title_fullStr | The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes |
| title_full_unstemmed | The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes |
| title_short | The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes |
| title_sort | common p r114w hnf4a mutation causes a distinct clinical subtype of monogenic diabetes |
| work_keys_str_mv | AT lavert thecommonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT colcloughk thecommonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT shepherdm thecommonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT patelk thecommonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT houghtonj thecommonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT dusatkovap thecommonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT pruhovas thecommonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT morrisa thecommonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT palmerc thecommonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT mccarthym thecommonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT ellards thecommonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT hattersleya thecommonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT weedonm thecommonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT lavert commonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT colcloughk commonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT shepherdm commonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT patelk commonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT houghtonj commonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT dusatkovap commonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT pruhovas commonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT morrisa commonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT palmerc commonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT mccarthym commonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT ellards commonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT hattersleya commonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes AT weedonm commonpr114whnf4amutationcausesadistinctclinicalsubtypeofmonogenicdiabetes |