Genotype-Based Severity Scoring System in Wolfram Syndrome: Correlation with Onset of Cardinal Symptoms and WFS1 Gene...

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 central diabetes insipidus (arginine-vasopressin deficiency). Our analysis revealed a clear association between the proposed genetic severity scoring system 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. To independently evaluate the proposed model, we developed a computational framework employing the classification rubric, which was able to confirm that the six-class system can be automatically annotated with 94.4% accuracy. Closer examination of the 7 cases that disagreed with the manual annotation helped improve the annotations and our scoring system, to deploy a three-class model, suggesting the value added by our automatic classifier. Taken together, these findings indicate that the genotype-based severity score is most informative for diabetes mellitus, more modestly informative for optic atrophy, and not currently useful for predicting the onset of hearing loss or diabetes insipidus. Because the analysis is based on observed events without time-to-event censoring and the three-tier consolidation is a post hoc summary of the same dataset, the results should be regarded as exploratory and hypothesis-generating rather than as a fully validated clinical prediction tool, while still offering useful insight into the genotype-related progression of Wolfram syndrome to guide future study.