Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders
Por:
Lee, EM, Verma, M, Palaniappan, N, Pope, EM, Lee, S, Blacher, L, Neerumalla, P, An, W, Campbell, T, Brown, C, Hurst, S, Marshall, B, Hershey, T, Nunes, V, de Heredia, ML, Urano, F
Publicada:
21 jun 2023
Resumen:
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.
Filiaciones:
Lee, EM:
Washington Univ, Dept Med, Div Endocrinol & Lipid Res, Sch Med, St Louis, MO 63110 USA
Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO 63110 USA
Washington Univ, Med Scientist Training Program, Sch Med, St Louis, MO USA
Verma, M:
Washington Univ, Dept Med, Div Endocrinol & Lipid Res, Sch Med, St Louis, MO 63110 USA
St Louis Univ, Sch Med, St Louis, MO USA
Palaniappan, N:
Washington Univ, Dept Med, Div Endocrinol & Lipid Res, Sch Med, St Louis, MO 63110 USA
Univ Missouri Kansas City, Sch Med, Kansas City, MO USA
Pope, EM:
Washington Univ, Dept Med, Div Endocrinol & Lipid Res, Sch Med, St Louis, MO 63110 USA
Lee, S:
Washington Univ, Dept Med, Div Endocrinol & Lipid Res, Sch Med, St Louis, MO 63110 USA
Blacher, L:
Washington Univ, Dept Med, Div Endocrinol & Lipid Res, Sch Med, St Louis, MO 63110 USA
Neerumalla, P:
Washington Univ, Dept Med, Div Endocrinol & Lipid Res, Sch Med, St Louis, MO 63110 USA
An, W:
Washington Univ, Dept Med, Div Endocrinol & Lipid Res, Sch Med, St Louis, MO 63110 USA
Campbell, T:
Washington Univ, Dept Med, Div Endocrinol & Lipid Res, Sch Med, St Louis, MO 63110 USA
Brown, C:
Washington Univ, Dept Med, Div Endocrinol & Lipid Res, Sch Med, St Louis, MO 63110 USA
Hurst, S:
Washington Univ, Dept Med, Div Endocrinol & Lipid Res, Sch Med, St Louis, MO 63110 USA
Marshall, B:
Washington Univ, Dept Pediat, Sch Med, St Louis, MO USA
Hershey, T:
Washington Univ, Dept Psychiat, Sch Med, St Louis, MO USA
Washington Univ, Dept Radiol, Sch Med, St Louis, MO USA
Nunes, V:
Genes Dis & Therapy Program IDIBELL, Mol Genet Lab, Barcelona, Spain
Univ Barcelona, Physiol Sci Dept, Genet Unit, Hlth Sci & Med Fac, Barcelona, Spain
de Heredia, ML:
Inst Salud Carlos III, Ctr Biomed Network Res Rare Dis CIBERER, Madrid, Spain
Urano, F:
Washington Univ, Dept Med, Div Endocrinol & Lipid Res, Sch Med, St Louis, MO 63110 USA
Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO 63110 USA
gold, Green Submitted
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