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dc.contributor.authorMalikova, Jana
dc.contributor.authorKaci, Alba
dc.contributor.authorDusatkova, Petra
dc.contributor.authorAukrust, Ingvild
dc.contributor.authorTorsvik, Janniche
dc.contributor.authorVesela, Klara
dc.contributor.authorKankova, Pavla
dc.contributor.authorNjølstad, Pål Rasmus
dc.contributor.authorPruhova, Stepanka
dc.contributor.authorBjørkhaug, Lise
dc.date.accessioned2021-02-10T12:23:17Z
dc.date.available2021-02-10T12:23:17Z
dc.date.created2020-02-18T09:04:11Z
dc.date.issued2020
dc.identifier.citationMalikova, J., Kaci, A., Dusatkova, P., Aukrust, I., Torsvik, J., Vesela, K., … Bjørkhaug, L. (2020). Functional analyses of HNF1A-MODY variants refine the interpretation of identified sequence variants. The Journal of Clinical Endocrinology & Metabolism, 105(4), e1377–e1386.en_US
dc.identifier.issn0021-972X
dc.identifier.urihttps://hdl.handle.net/11250/2727191
dc.descriptionThis is an Author's Accepted Manuscript Version (postprint) of an article published by Oxford University Press in The Journal of Clinical Endocrinology & Metabolism, available from https://doi.org/10.1210/clinem/dgaa051en_US
dc.description.abstractContext While rare variants of the hepatocyte nuclear factor-1 alpha (HNF1A) gene can cause maturity-onset diabetes of the young (HNF1A-MODY), other variants can be risk factors for the development of type 2 diabetes. As has been suggested by the American College of Medical Genetics (ACMG) guidelines for variant interpretation, functional studies provide strong evidence to classify a variant as pathogenic. Objective We hypothesized that a functional evaluation can improve the interpretation of the HNF1A variants in our Czech MODY Registry. Design, Settings, and Participants We studied 17 HNF1A variants that were identified in 48 individuals (33 female/15 male) from 20 Czech families with diabetes, using bioinformatics in silico tools and functional protein analyses (transactivation, protein expression, DNA binding, and nuclear localization). Results Of the 17 variants, 12 variants (p.Lys120Glu, p.Gln130Glu, p.Arg131Pro, p.Leu139Pro, p.Met154Ile, p.Gln170Ter, p.Glu187SerfsTer40, p.Phe215SerfsTer18, p.Gly253Arg, p.Leu383ArgfsTer3, p.Gly437Val, and p.Thr563HisfsTer85) exhibited significantly reduced transcriptional activity or DNA binding (< 40%) and were classified as (likely) pathogenic, 2/17 variants were (likely) benign and 3/17 remained of uncertain significance. Functional analyses allowed for the reclassification of 10/17 variants (59%). Diabetes treatment was improved in 20/29 (69%) carriers of (likely) pathogenic HNF1A variants. Conclusion Functional evaluation of the HNF1A variants is necessary to better predict the pathogenic effects and to improve the diagnostic interpretation and treatment, particularly in cases where the cosegregation or family history data are not available or where the phenotype is more diverse and overlaps with other types of diabetes.en_US
dc.language.isoengen_US
dc.publisherOxford University Pressen_US
dc.subjectACMG classificationen_US
dc.subjectfunctional studyen_US
dc.subjectHNF1A-MODYen_US
dc.subjecthepatocyte nuclear factor-1 alpha variantsen_US
dc.subjectreclassificationen_US
dc.titleFunctional Analyses of HNF1A-MODY Variants Refine the Interpretation of Identified Sequence Variantsen_US
dc.typePeer revieweden_US
dc.typeJournal articleen_US
dc.description.versionacceptedVersionen_US
dc.source.pagenumbere1377-e1386en_US
dc.source.volume105en_US
dc.source.journalJournal of Clinical Endocrinology and Metabolismen_US
dc.source.issue4en_US
dc.identifier.doi10.1210/clinem/dgaa051
dc.identifier.cristin1795068
dc.relation.projectNorges forskningsråd: 240413en_US
dc.relation.projectMinistry of Health of the Czech Republic: NV18-01-00078en_US
cristin.ispublishedtrue
cristin.fulltextpostprint
cristin.qualitycode2


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