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Improving detection of monogenic diabetes through reanalysis of <i>GCK</i> variants of uncertain significance

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dc.contributor.authorDe Sousa, S.M.C.
dc.contributor.authorPhan, J.M.N.
dc.contributor.authorWells, A.
dc.contributor.authorWu, K.H.C.
dc.contributor.authorScott, H.S.
dc.date.issued2025
dc.descriptionLink to a related website: https://doi.org/10.1007/s00592-025-02467-6, Correction
dc.description.abstract<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Aims</jats:title> <jats:p>To assess the utility of reanalysing <jats:italic>GCK</jats:italic> variants of uncertain significance (VUS) as an intervention to improve the detection of monogenic diabetes.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>We examined <jats:italic>GCK</jats:italic> VUS in a local cohort of individuals with suspected monogenic diabetes and re-curated each variant against the recent ClinGen <jats:italic>GCK</jats:italic>-specific variant classification guidelines.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Variant reanalysis achieved a new ‘likely pathogenic’ classification (i.e., positive results) in 4/8 identified VUS. The single most common newly applied criterion indicating variant pathogenicity was a confirmed phenotype of <jats:italic>GCK</jats:italic>-hyperglycaemia. RNA sequencing and segregation studies were performed in two cases but not additive to reclassification.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>This is the first VUS reclassification study in monogenic diabetes using gene-specific guidelines. Within the limits of this small study, we observed a high rate (50%) of VUS upgrades to a positive result, thereby confirming the utility of VUS reanalysis– particularly with biochemical phenotyping– in increasing the detection of monogenic diabetes. We recommend HbA1c, fasting blood glucose and either pancreatic autoantibody negativity or a small oral glucose tolerance test increment as a feasible minimum dataset to inform variant classification at the individual patient level, noting the ongoing work of the ClinGen Monogenic Diabetes Expert Panel in systematically reviewing <jats:italic>GCK</jats:italic> variants at the international level.</jats:p> </jats:sec>
dc.identifier.citationActa Diabetologica, online, 2025; online(8)
dc.identifier.doi10.1007/s00592-025-02449-8
dc.identifier.issn0940-5429
dc.identifier.issn1432-5233
dc.identifier.orcidDe Sousa, S.M.C. [0000-0003-0127-6482]
dc.identifier.orcidScott, H.S. [0000-0002-5813-631X]
dc.identifier.urihttps://hdl.handle.net/11541.2/41733
dc.language.isoen
dc.publisherSPRINGER-VERLAG ITALIA SRL
dc.relation.fundingRoyal Adelaide Hospital Mary Overton Early Career Research Fellowship
dc.relation.fundingRoyal Australasian College of Physicians Fellows Research Establishment Fellowship
dc.relation.fundingEndocrine Society of Australia Postdoctoral Award
dc.rightsCopyright 2025 The Authors. (http://creativecommons.org/licenses/by/4.0/) Access Condition Notes: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
dc.source.urihttps://doi.org/10.1007/s00592-025-02449-8
dc.subjectDNA sequencing
dc.subjectgenetics
dc.subjectglucokinase
dc.subjectmonogenic diabetes
dc.titleImproving detection of monogenic diabetes through reanalysis of <i>GCK</i> variants of uncertain significance
dc.typeJournal article
pubs.publication-statusPublished online
ror.fileinfo12298692980001831 13298692970001831 s00592-025-02449-8
ror.mmsid9916945731201831

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