The Common p.R114W HNF4A Mutation Causes a Distinct Clinical Subtype of Monogenic Diabetes

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• HNF4A mutations are linked to increased birth weight, neonatal hypoglycemia, and Maturity Onset Diabetes of the Young (MODY).
• The p.R114W variant is frequently reported but its pathogenicity and clinical impact remain debated due to inconsistent functional data and variable penetrance.

Purpose of the Study:

• To confirm the pathogenicity of the HNF4A p.R114W mutation.
• To characterize the distinct clinical phenotype associated with HNF4A p.R114W.
• To evaluate the penetrance and treatment response of HNF4A p.R114W heterozygotes.

Main Methods:

• Case-control study comparing HNF4A p.R114W heterozygotes with control subjects and patients with other HNF4A mutations.
• Analysis of clinical data including birth weight, diabetes development, and response to sulfonylurea treatment.
• Statistical analysis to determine odds ratios, penetrance, and significance of observed differences.

Main Results:

• HNF4A p.R114W is confirmed as a pathogenic mutation for diabetes with a high odds ratio (30.4).
• p.R114W heterozygotes show reduced penetrance (54% by age 30) and do not exhibit increased birth weight compared to other HNF4A mutations.
• A lower proportion of p.R114W patients responded to sulfonylurea treatment (48%) compared to other HNF4A mutations (73%).

Conclusions:

• HNF4A p.R114W represents a distinct subtype of HNF4A MODY characterized by reduced penetrance, lack of effect on birth weight, and decreased sensitivity to sulfonylurea.
• These findings have significant implications for the diagnosis, management, and genetic counseling of individuals and families affected by HNF4A-related diabetes.
• The study highlights the potential for identifying similar rare, low-penetrance MODY mutations as large-scale sequencing data becomes more accessible.