Genotype and Clinical Characteristics of Patients with Wolfram Syndrome and WFS1-related Disorders

Abstract

Objective: Wolfram syndrome (WFS) is an autosomal recessive disorder associated with juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. We sought to elucidate the relationship between genotypic and phenotypic presentations of Wolfram syndrome which would assist clinicians in classifying the severity and prognosis of Wolfram syndrome more accurately.

Approach: Patient data from the Washington University International Registry and Clinical Study for Wolfram Syndrome and patient case reports were analyzed to select for patients with two recessive mutations in the WFS1 gene. Mutations were classified as being either nonsense/frameshift variants or missense/in-frame insertion/deletion variants and statistical analysis was performed using unpaired and paired t-tests and one- and two-way ANOVA with Tukey's or Dunnett's tests.

Results: A greater number of genotype variants correlated with earlier onset and a more severe presentation of Wolfram syndrome. Secondly, non-sense and frameshift variants had more severe phenotypic presentations than missense variants, as evidenced by optic atrophy emerging significantly earlier in patients with 2 nonsense/frameshift alleles compared with 0 missense transmembrane variants. In addition, the number of transmembrane in-frame variants demonstrated a statistically significant dose-effect on age of onset of diabetes mellitus and optic atrophy.

Summary / conclusions: The results contribute to our current understanding of the genotype-phenotype relationship of Wolfram syndrome, suggesting that alterations in coding sequences result in significant changes in the presentation and severity of Wolfram. The impact of these findings is significant, as the results will aid clinicians in predicting more accurate prognoses and pave the way for personalized treatments for Wolfram syndrome.

Figure 1.. Mean age of onset of clinical manifestations of Wolfram Syndrome.

Diabetes mellitus, optic atrophy, diabetes insipidus, and hearing loss emerged respectively at mean ages of 7.5, 12.9, 14.1, and 15.3 years.

Figure 2.. Analysis of genotype-phenotype correlations for number of nonsense/frameshift variants.

Age of onset of different clinical manifestations by number of nonsense/frameshift variants vs in-frame missense or insertion/deletion variants for the entire dataset (A) and split by patient sex (B). NSFS2: two nonsense/frameshift variants (n=65-129). NSFS1: one nonsense/frameshift variant (n=39-87). IF: no nonsense/frameshift variants (n=47-111). *, P<0.05; **, P<0.01; ***, P<0.001; n.s., no significance. P-values were assigned using Wilcoxon’s Rank Sum Test with multiple test correction applied via the Bonferroni method.

Figure 3.. Analysis of genotype-phenotype correlations for in-frame variants by transmembrane/non-transmembrane domain.

Age of onset of different clinical manifestations by number of in-frame variants (either missense or in-frame insertion/deletion) in transmembrane domains for patients with two in-frame variants (A) and patients with one in-frame variant (B). 2TM: Two transmembrane variants (n=24-42). 1TM: One transmembrane variant (n=7-24). NTM: No transmembrane variants (n=16-45). *, P<0.05; **, P<0.01; n.s., no significance. P-values were assigned using Wilcoxon’s Rank Sum Test with multiple test correction applied via the Bonferroni method.