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

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. ### Competing Interest Statement FU is an inventor of three patents related to the treatment of Wolfram syndrome, US 9,891,231 SOLUBLE MANF IN PANCREATIC BETA CELL DISORDERS and US 10,441,574 and US 10,695,324 TREATMENT FOR WOLFRAM SYNDROME AND OTHER ER STRESS DISORDERS. FU is a Founder and President of CURE4WOLFRAM, INC. FU is the Chair of the Scientific Advisory Board for Opris Biotechnologies. ### Funding Statement This work was partly supported by grants from the National Institutes of Health (NIH)/NIDDK (DK132090, DK020579), NIH/ National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), and philanthropic supports from the Silberman Fund, the Ellie White Foundation for the Rare Genetic Disorders, the Snow Foundation, the Unravel Wolfram Syndrome Fund, the Stowe Fund, the Feiock Fund, the Cachia Fund, the Gildenhorn Fund, the Eye Hope Foundation, the Gadot Fund, Ontario Wolfram League, Associazione Gentian - Sindrome di Wolfram Italia, Alianza de Familias Afectadas por el Sindrome Wolfram Spain, Wolfram syndrome UK, and Association Syndrome de Wolfram France to F. Urano. Research reported in this publication was also supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the NIH/NCATS. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. The authors thank all the members of the Washington University Wolfram Syndrome Study and Research Clinic for their support () and all the participants in the Wolfram syndrome International Registry and Clinical Study, Research Clinic, and Clinical Trials for their time and efforts. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Study approval. For human study, patients and their parents or legal guardians, as appropriate, provided written informed consent before participating in this study, which was approved by the Human Research Protection Office at Washington University School of Medicine in St. Louis (IRB ID 201107067). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors