GNE genotype explains 20% of phenotypic variability in GNE myopathy
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- dc.contributor.author Pogoryelova, Oksana
- dc.contributor.author Wilson, Ian J.
- dc.contributor.author Mansbach, Hank
- dc.contributor.author Argov, Zohar
- dc.contributor.author Nishino, Ichizo
- dc.contributor.author Lochmüller, Hanns
- dc.date.accessioned 2020-04-03T07:28:48Z
- dc.date.available 2020-04-03T07:28:48Z
- dc.date.issued 2019
- dc.description.abstract Objective: To test the hypothesis that common GNE mutations influence disease severity; using statistical analysis of patient cohorts from different countries. Methods: Systematic literature review identified 11 articles reporting 759 patients. GNE registry data were used as a second data set. The relative contributions of the GNE mutations, homozygosity, and country to the age at onset were explored using linear modeling, and relative importance measures were calculated. The rate of ambulation loss for GNE mutations, homozygosity, country, and age at onset was analyzed using Cox proportional hazards models. Results: A spectrum of symptoms and large variability of age at onset and nonambulatory status was observed within families and cohorts. We estimated that 20% of variability is explained by GNE mutations. Individuals harboring p.Asp207Val have an expected age at onset 8.0 (s.e1.0) years later than those without and probability of continued ambulation at age 40 of 0.98 (95% confidence interval [CI] 0.96–1). In contrast, p.Leu539Ser results in onset on average 7.2 (s.e.2.7) years earlier than those without this mutation, and p.Val603Leu has a probability of continued ambulance of 0.61 (95% CI 0.50–0.74) at age 40, but has a nonsignificant effect on age at onset. Conclusions: GNE myopathy severity significantly varies in all cohorts, with 20% of variability explained by the GNE mutation. Atypical symptoms and clinical presentation suggest that physical and instrumental examination should include additional clinical tests. Proven and measurable effect of GNE mutations on the disease severity should be factored in patient management and clinical research study for a better data interpretation.
- dc.description.sponsorship This work was supported by European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 305444 (RD-Connect) and Medical Research Council UK (reference G1002274, grant ID 98482).
- dc.format.mimetype application/pdf
- dc.identifier.citation Pogoryelova O, Wilson IJ, Mansbach H, Argov Z, Nishino I, Lochmüller H. GNE genotype explains 20% of phenotypic variability in GNE myopathy. Neurol Genet. 2019; 5(1):e308. DOI: 10.1212/NXG.0000000000000308
- dc.identifier.doi http://dx.doi.org/10.1212/NXG.0000000000000308
- dc.identifier.issn 2376-7839
- dc.identifier.uri http://hdl.handle.net/10230/44157
- dc.language.iso eng
- dc.publisher Wolters Kluwer (LWW)
- dc.relation.ispartof Neurol Genet. 2019; 5(1):e308
- dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305444
- dc.rights © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- dc.subject.keyword All Genetics
- dc.subject.keyword Cohort studies
- dc.subject.keyword Association studies in genetics
- dc.subject.keyword Natural history studies (prognosis)
- dc.subject.keyword Muscle disease
- dc.title GNE genotype explains 20% of phenotypic variability in GNE myopathy
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion