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

Autor:	Lee EM; Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.; Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110, USA., Verma M; Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.; Saint Louis University School of Medicine, Saint Louis, MO, USA., Palaniappan N; Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.; University of Missouri Kansas City, Kansas City, MO, USA., Pope EM; Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.; Massachusetts Institute of Technology, Cambridge, MA, USA., Lee S; Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.; Cornell University, Ithaca, NY, USA., Blacher L; Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA., Neerumalla P; Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA., An W; Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA., Campbell T; Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA., Brown C; Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA., Hurst S; Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA., Marshall B; Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA., Hershey T; Departments of Psychiatry and Radiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA., Nunes V; Molecular Genetics Laboratory. Genes, Disease and Therapy Program IDIBELL, l'Hospitalet de Llobregat, Barcelona, Spain.; Genetics Unit. Physiological Sciences Department. Health Sciences and Medicine Faculty. University of Barcelona, l'Hospitalet de Llobregat, Barcelona, Spain., de Heredia ML; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain., Urano F; Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.; Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2023 Feb 16. Date of Electronic Publication: 2023 Feb 16.
DOI:	10.1101/2023.02.15.23284904
Abstrakt:	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.
Databáze:	MEDLINE
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