Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders
Lee, Evan M. (Washington University School of Medicine)
Verma, Megha (Saint Louis University School of Medicine)
Palaniappan, Nila (University of Missouri Kansas City)
Pope, Emiko M. (Washington University School of Medicine)
Lee, Sammie (Washington University School of Medicine)
Blacher, Lindsey (Washington University School of Medicine)
Neerumalla, Pooja (Washington University School of Medicine)
An, William (Washington University School of Medicine)
Campbell, Toko (Washington University School of Medicine)
Brown, Cris (Washington University School of Medicine)
Hurst, Stacy (Washington University School of Medicine)
Marshall, Bess (Washington University School of Medicine)
Hershey, Tamara (Washington University School of Medicine)
Nunes Martínez, Virginia (Hospital Universitari de Bellvitge)
López de Heredia, Miguel (Institut d'Investigació Biomèdica Sant Pau)
Urano, Fumihiko (Washington University School of Medicine)
Universitat Autònoma de Barcelona

Data:	2023
Resum:	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. 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. 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. 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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	WFS1-related disorders ; Diabetes insipidus ; Diabetes mellitus ; Genotype phenotype correlation ; Hearing loss ; Optic atrophy ; Wolfram syndrome
Publicat a:	Frontiers in genetics, Vol. 14 (2023) , p. 1198171, ISSN 1664-8021

DOI: 10.3389/fgene.2023.1198171
PMID: 37415600

12 p, 1.8 MB

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