Novel WFS1 variants are associated with different diabetes phenotypes

Area of Science:

• Genetics
• Molecular Biology
• Endocrinology

Background:

• The WFS1 gene encodes wolframin, essential for endoplasmic reticulum (ER) homeostasis.
• WFS1 variants are linked to Wolfram syndrome, diabetes mellitus, and psychiatric diseases, often leading to misdiagnosis.
• Understanding WFS1's role is critical for diagnosing complex genetic disorders.

Purpose of the Study:

• To investigate the role of WFS1 gene variants in patients with early-onset unclassified diabetes.
• To evaluate the functional impact of identified WFS1 compound heterozygous variants.
• To highlight the clinical significance of WFS1 variants in ER stress-related disorders.

Main Methods:

• Whole-exome sequencing (WES) was performed on 165 patients with early-onset diabetes.
• Variant interpretation followed ACMG/AMP 2015 guidelines, with verification by Sanger sequencing.
• In vitro experiments assessed the functional effects of WFS1 compound heterozygous variants on ER stress and cell viability.

Main Results:

• WFS1 compound heterozygous variants (p.A214fs*74/p.F329I and p.I427S/p.I304T) were identified in two patients with Wolfram Syndrome-Like disorders (WSLD).
• These variants increased ER stress, reduced cell viability, and decreased SERCA2b mRNA levels.
• Pathogenic or likely pathogenic WFS1 heterozygous variants were found in three additional patients.

Conclusions:

• Early genetic testing for WFS1 variants is crucial for diagnosing young-onset diabetes and WSLD.
• WFS1 variants contribute to ER stress and reduced cell viability, impacting clinical outcomes.
• Integrating genetic findings into clinical practice can reduce misdiagnoses and refine treatment strategies.