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. Missense/in-frame variants were further classified as transmembrane or non-transmembrane based on whether they affected amino acid residues predicted to be in transmembrane domains of WFS1. Statistical analysis was performed using Wilcoxon rank-sum tests with multiple test adjustment applied via the Bonferonni correction. 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 diabetes mellitus and optic atrophy emerging significantly earlier in patients with two nonsense/frameshift variants compared with zero or one nonsense/frameshift 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 among patients with either one or two in-frame variants. Summary/Conclusion: 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.

Keywords: WFS1-related disorders; diabetes insipidus; diabetes mellitus; genotype phenotype correlation; hearing loss; optic atrophy; wolfram syndrome.

FIGURE 1

Median age of onset of clinical manifestations of Wolfram Syndrome. Diabetes mellitus, optic atrophy, diabetes insipidus, and hearing loss emerged respectively at median ages of 6.0, 11.0, 13.0, and 14.0 years. Box plots show the following for onset age of each clinical manifestation: inner line, median; box edges, quartiles; whiskers, 1.5x interquartile range; individual points, outliers (defined as outside 1.5x interquartile range). The sample size (n) for each clinical manifestation is shown along the x-axis.

FIGURE 2

Analysis of genotype-phenotype correlations for number nonsense/frameshift variants. Age of onset of different clinical manifestations by number of nonsense/frameshift (NSFS) variants vs. in-frame missense or insertion/deletion variants for the entire dataset (A) and split by patient sex (B). The sample size (n) for each group for each clinical manifestation is shown along the x-axis. *, p < 0.05; **, p < 0.01; ***, p < 0.001; n.s., no significance. p-values were assigned using Wilcoxon Rank Sum Test with multiple test correction applied via the Bonferroni method. Box plots show the following for onset age of each clinical manifestation within each group: inner line, median; box edges, quartiles; whiskers, 1.5x interquartile range; individual points, outliers (defined as outside 1.5x interquartile range).

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). The sample size (n) for each group for each clinical manifestation is shown along the x-axis. p < 0.05; **, p < 0.01; n.s., no significance. p-values were assigned using Wilcoxon Rank Sum Test with multiple test correction applied via the Bonferroni method. Box plots show the following for onset age of each clinical manifestation within each group: inner line, median; box edges, quartiles; whiskers, 1.5x interquartile range; individual points, outliers (defined as outside 1.5x interquartile range).

FIGURE 4

Schema of severity of Wolfram-Syndrome and Wolfram-related disorders. (A) Severity and clinical manifestations of Wolfram-related disorders and Wolfram Syndrome. (B) Severity of Wolfram Syndrome based on variant number and effect on coding sequence or transmembrane domain positions.