ArticleDiabetes2016
The Common p.R114W HNF4A Mutation Causes a Distinct Clinical Subtype of Monogenic Diabetes.
Article in Diabetes, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 2 of them syntheses that pooled it.
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Who cites it
34 citing papers in PubMed, 2 syntheses or guidelines pooled it, 57 citations in OpenAlex.
- Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes.Nature genetics · 2024Pooled it
- Evidence for penetrance in patients without a family history of disease: a systematic review.European journal of human genetics : EJHG · 2020Pooled it
- Global perspectives on monogenic forms of diabetes.Diabetologia · 2025Review
- Hidden MODY in Young Lean Women with Mild Glucose Intolerance Detected during Health Check-ups: Potential for Improved Pregnancy Outcomes through Preconception Care.Internal medicine (Tokyo, Japan) · 2025Article
- Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM.Biomolecules · 2025Review
- Parsing the spectrum of allelic architectures in diabetes.Nature genetics · 2024Article
- Guidance for estimating penetrance of monogenic disease-causing variants in population cohorts.Nature genetics · 2024Review
- Molecular mechanism of HNF-1A-mediated HNF4A gene regulation and promoter-driven HNF4A-MODY diabetes.JCI insight · 2024Article
- Functional characterization of HNF4A gene variants identify promoter and cell line specific transactivation effects.Human molecular genetics · 2024Article
- Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion.Communications medicine · 2023Article
- Incomplete penetrance and variable expressivity in monogenic diabetes; a challenge but also an opportunity.Reviews in endocrine & metabolic disorders · 2023Review
- Identification and precision therapy for three maturity-onset diabetes of the young (MODY) families caused by mutations in the HNF4A gene.Frontiers in endocrinology · 2023Article
- Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.American journal of human genetics · 2022Article
- Insights into the Genetics and Signaling Pathways in Maturity-Onset Diabetes of the Young.International journal of molecular sciences · 2022Review
- How do I diagnose Maturity Onset Diabetes of the Young in my patients?Clinical endocrinology · 2022Review
- Gain of Function of Malate Dehydrogenase 2 and Familial Hyperglycemia.The Journal of clinical endocrinology and metabolism · 2022Observational
- Association of birthweight and penetrance of diabetes in individuals with HNF4A-MODY: a cohort study.Diabetologia · 2022Article
- Identification of two novel subgroups in patients with diabetes mellitus and their association with clinical outcomes: A two-step cluster analysis.Journal of diabetes investigation · 2021Article
- NGS Analysis Revealed Digenic HeterozygousDiagnostics (Basel, Switzerland) · 2021Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
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.
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