HNF1A-Maturity-Onset Diabetes of the Young (MODY) in a Family With a Rare Silent Variant: Clinical Challenges and Variable Expressivity
Year: 2026
Type: article
Study design: Case Report
Abstract: Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance, typically occurring during adolescence or early adulthood. Mutations in the hepatocyte nuclear factor 1-α (HNF1A) gene are among the most common causes of MODY and are frequently misdiagnosed as type 1 (T1D) or type 2 diabetes (T2D), leading to inappropriate management. We report the case of a preschool-aged boy who presented with polyuria and polydipsia, fasting hyperglycemia, negative pancreatic autoantibodies, and an elevated C-peptide level. A multi-generational family history of diabetes was noted, and his older sister was previously diagnosed with T2D. Genetic testing using direct sequencing identified a rare heterozygous silent variant in exon 8 of the HNF1A gene (c.1533G>A; p. Gln511=) in the index patient, his sister, and his mother. To date, the mother remains entirely asymptomatic and normoglycemic. The variant is exceptionally rare in global population databases. Both siblings have maintained optimal glycemic control for four years through dietary modification alone, without requiring pharmacological therapy. This case demonstrates that rare silent HNF1A variants can be clinically pathogenic, likely by disrupting pre-mRNA splicing kinetics or mRNA stability. The observed familial segregation strongly suggests a clinical pattern of incomplete penetrance (an asymptomatic maternal carrier) and variable expressivity, potentially pointing to an attenuated, partial genetic defect rather than a complete loss of function. This case underscores the importance of integrating rigorous clinical phenotyping and familial segregation tracking alongside automated in silico predictions when evaluating synonymous variants in suspected monogenic diabetes.
Source: Cureus
Authors: Rita Carvalho, Biana Moreira, Susana Parente
Institution: Unidade Local de Saúde da Arrábida
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7165117928