Genotype-Based Severity Scoring System in Wolfram Syndrome

Wolfram syndrome is a rare genetic disorder characterized by antibody-negative early-onset atypical diabetes mellitus, optic nerve atrophy, sensorineural hearing loss, diabetes insipidus (arginine vasopressin deficiency), and progressive neurodegeneration, with significant variability in disease severity. We assessed the accuracy of a genotype-based severity scoring system to predict the onset of cardinal symptoms in Wolfram syndrome. This system is based on the type of WFS1 variants (in-frame or out-of-frame) and their location relative to transmembrane domains. Severity scores were assigned to 324 patients with documented onset ages for diabetes mellitus, optic atrophy, hearing loss, and diabetes insipidus. Our analysis revealed a clear correlation between severity scores and earlier onset of diabetes mellitus and optic atrophy. Patients with in-frame variants outside transmembrane domains exhibited milder symptoms, especially WFS1 c.1672C>T (p.Arg558Cys) variant, whereas those with out-of-frame variants showed the earliest onset. Severity scores 3 and 4 did not follow the expected progression, suggesting that transmembrane domain involvement in both alleles may result in greater severity. These findings suggest that this scoring system provides valuable insights into the progression of Wolfram syndrome and may guide clinical care. Further refinement may improve its utility for predicting the onset of non-diabetic symptoms.