ArticleDiabetologia2022
A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY.
Article in Diabetologia, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 21 citations in OpenAlex.
- Effect of SGLT2 Inhibition on Glucosuria During a Hyperglycemic Clamp in HNF1A-MODY (MODY3) and Type 2 Diabetes.Diabetes care · 2025Trial
- Polygenic background contributes to GCK-MODY clinical presentation and glycaemic variability.Diabetologia · 2026Article
- Population Prevalence, Penetrance, and Mortality for Genetically Confirmed MODY.The Journal of clinical endocrinology and metabolism · 2026Article
- The conundrum in diagnosing Maturity-Onset Diabetes of the Young (MODY) in a large German pedigree with early-onset diabetes and a novel HNF1A variant.Molecular and cellular pediatrics · 2026Article
- Phenotypic heterogeneity and polygenic risk scores in a family of maturity-onset diabetes of the young.JCEM case reports · 2026Article
- MODY Is Prevalent in Later-Onset Diabetes and Has Potential for Targeted Therapy but Is Challenging to Identify.Diabetes · 2026Article
- Hepatocyte nuclear factor 1 in renal lipid metabolism: molecular mechanisms and therapeutic potentials.Cell biology and toxicology · 2025Review
- Polygenic determinants of monogenic diabetes.Nature metabolism · 2025Article
- Common genetic variants modify disease risk and clinical presentation in monogenic diabetes.Nature metabolism · 2025Article
- Maturity onset diabetes of the young and beyond: the changing face of single-gene diabetes.European journal of endocrinology · 2025Review
- A polygenic risk score derived from common variants of monogenic diabetes genes is associated with young-onset type 2 diabetes and cardiovascular-kidney complications.Diabetologia · 2025Article
- Genetic Characterization of MODY in Iranian Families Using Multigenerational-Based Whole-Exome Sequencing Approach.Journal of diabetes research · 2025Article
- Young-Onset Diabetes in East Asians: From Epidemiology to Precision Medicine.Endocrinology and metabolism (Seoul, Korea) · 2024Review
- Incomplete penetrance and variable expressivity in monogenic diabetes; a challenge but also an opportunity.Reviews in endocrine & metabolic disorders · 2023Review
- Monogenic diabetes.Nature reviews. Disease primers · 2023Review
- Article
- Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.American journal of human genetics · 2022Article
- Achievements, prospects and challenges in precision care for monogenic insulin-deficient and insulin-resistant diabetes.Diabetologia · 2022Review
Corrections and comments
- Erratum issued
Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisSystematic studies on the phenotypic consequences of variants causal of HNF1A-MODY are rare. Our aim was to assess the phenotype of carriers of a single HNF1A variant and genetic and clinical factors affecting the clinical spectrum.
methodsWe conducted a family-based multigenerational study by comparing heterozygous carriers of the HNF1A p.(Gly292fs) variant with the non-carrier relatives irrespective of diabetes status. During more than two decades, 145 carriers and 131 non-carriers from 12 families participated in the study, and 208 underwent an OGTT at least once. We assessed the polygenic risk score for type 2 diabetes, age at onset of diabetes and measures of body composition, as well as plasma glucose, serum insulin, proinsulin, C-peptide, glucagon and NEFA response during the OGTT.
resultsHalf of the carriers remained free of diabetes at 23 years, one-third at 33 years and 13% even at 50 years. The median age at diagnosis was 21 years (IQR 17-35). We could not identify clinical factors affecting the age at conversion; sex, BMI, insulin sensitivity or parental carrier status had no significant effect. However, for 1 SD unit increase of a polygenic risk score for type 2 diabetes, the predicted age at diagnosis decreased by 3.2 years. During the OGTT, the carriers had higher levels of plasma glucose and lower levels of serum insulin and C-peptide than the non-carriers. The carriers were also leaner than the non-carriers (by 5.0 kg, p=0.012, and by 2.1 kg/m CONCLUSIONS/
interpretationThe most common causal variant of HNF1A-MODY, p.(Gly292fs), presents not only with hyperglycaemia and insulin deficiency, but also with increased lipolysis and markedly lower adult BMI. Serum insulin was more discriminative than C-peptide between carriers and non-carriers. A considerable proportion of carriers develop diabetes after young adulthood. Even among individuals with a monogenic form of diabetes, polygenic risk of diabetes modifies the age at onset of diabetes.
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