In Silico Analysis Identified Putative Pathogenic Missense Single Nucleotide Polymorphisms (SNPs) in the Human HNF1A...

Area of Science:

• Genetics
• Molecular Biology
• Endocrinology

Background:

• Maturity-onset diabetes of the young (MODY) is a rare genetic diabetes.
• MODY-3 is associated with the HNF1A gene, but causative variants and mechanisms are often unclear.
• Investigating HNF1A variants with uncertain clinical significance is crucial for understanding MODY-3.

Purpose of the Study:

• To investigate HNF1A missense variants with clinical uncertainty.
• To identify pathogenic variants contributing to MODY-3 using bioinformatics tools.
• To enhance the interpretation of genetic variants in diabetes.

Main Methods:

• Utilized bioinformatics tools to analyze HNF1A missense variants from GnomAD v4.1.0.
• Filtered 2444 uncertain variants down to 138 missense variants.
• Assessed variant pathogenicity, allele frequency, secondary structure, protein stability, and 3D structure.

Main Results:

• Four HNF1A variants (Arg168Cys, Glu275Ala, Gly375Asp, Val411Phe) were consistently predicted as pathogenic.
• These variants showed very low allele frequencies globally.
• Predicted structural changes and decreased protein stability for these variants, with conserved amino acids at variation sites.

Conclusions:

• Identified 4 consistently pathogenic HNF1A missense variants among 138 of uncertain significance.
• Findings support variant interpretation and understanding genotype-phenotype associations in diabetes.
• Aims to improve healthcare for patients with diabetes by clarifying genetic causes.