ArticleAmerican journal of human genetics2022
Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers, 1 of them a synthesis that pooled it.
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Who cites it
68 citing papers in PubMed, 1 synthesis or guideline pooled it, 91 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
- Prevalence and penetrance of heritable retinoblastoma in two adult population cohorts: implications for genomic newborn screening.European journal of human genetics : EJHG · 2026Article
- The central role of the β-cell in diabetes: from monogenic forms to type 1, type 2, and gestational diabetes.Reviews in endocrine & metabolic disorders · 2026Review
- Genetic spectrum and treatment implications of maturity-onset diabetes of the young in the eastern Black Sea region of Türkiye: a combined adult and pediatric cohort of 296 patients with identification of rare and novel variants.Molecular biology reports · 2026Article
- Polygenic background contributes to GCK-MODY clinical presentation and glycaemic variability.Diabetologia · 2026Article
- Pediatric Genomic Medicine-rapid progress, but not too fast: American Pediatric Society's 2026 John Howland Award Lecture.Pediatric research · 2026Article
- Cancer risk in adults with pathogenic germline variants in RAS/MAPK genes using genomic ascertainment.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Evaluation of rare NR1D2 variants in MODY-X: clinical, genetic, and in silico insights.Journal of endocrinological investigation · 2026Article
- Uncovering apparent incomplete penetrance of TSC1/TSC2 variants: Insights from multiple population cohorts and implications for newborn screening.European journal of human genetics : EJHG · 2026Article
- From clinical genetics to genomic-based public health screening programmes: duty-based ethics as a guide for responsible implementation.European journal of human genetics : EJHG · 2026Article
- Reduced penetrance of COL1A1/2 pathogenic variants linked with osteogenesis imperfecta: analysis of a large population cohort.European journal of human genetics : EJHG · 2026Article
- Population Prevalence, Penetrance, and Mortality for Genetically Confirmed MODY.The Journal of clinical endocrinology and metabolism · 2026Article
- Maturity Onset Diabetes of the Young (MODY): French National Diagnosis and Care Protocol (PNDS, Protocole National de Diagnostic et de Soins).Orphanet journal of rare diseases · 2026Review
- Molecular diagnosis of maturity-onset diabetes of the young via whole-exome sequencing: a cohort study in Taizhou, China.Endocrine · 2026Article
- A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data.EMBO molecular medicine · 2026Article
- MODY Is Prevalent in Later-Onset Diabetes and Has Potential for Targeted Therapy but Is Challenging to Identify.Diabetes · 2026Article
- Low population penetrance of variants associated with inherited retinal degenerations.American journal of human genetics · 2026Article
- Residual allelic activity likely underlies the low rates of disease expression for predicted loss-of-function variants in population-scale biobanks.American journal of human genetics · 2025Article
- Sulphonylurea efficacy and end-organ outcomes in the management of HNF4A-MODY.Diabetic medicine : a journal of the British Diabetic Association · 2025Article
- Antibody-Positive Type 1 Diabetes in a Family With a PathogenicJCEM case reports · 2025Article
8 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the penetrance and prevalence of pathogenic variants in HNF1A, HNF4A, and GCK that account for >80% of monogenic diabetes. We analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort (n = 132,194), and a UK population-based cohort (n = 198,748). We show that one in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts highlighting the role of environment/other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar across all cohorts (89%-97%). We highlight that pathogenic variants in HNF1A, HNF4A, and GCK are not ultra-rare in the population. For HNF1A and HNF4A, we need to tailor genetic interpretation and counseling based on the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. This along with the clinical implication of diagnosis makes it an excellent candidate for the American College of Medical Genetics secondary gene list.
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