Sunita M. C. De Sousa1,2,3 · Jennifer M. N. Phan4,5 · Amanda Wells4 · Kathy H. C. Wu6,7,8,9 · Hamish S. Scott1,4,10
Received: 12 December 2024 / Accepted: 3 January 2025 / Published online: 16 January 2025 © The Author(s) 2025, corrected publication 2025
Abstract
Aims To assess the utility of reanalysing GCK variants of uncertain significance (VUS) as an intervention to improve the detection of monogenic diabetes.
Methods We examined GCK VUS in a local cohort of individuals with suspected monogenic diabetes and re-curated each variant against the recent ClinGen GCK-specific variant classification guidelines.
Results 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 GCK-hyperglycaemia. RNA sequencing and segregation studies were performed in two cases but not additive to reclassification.
Conclusions 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 util-ity 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 GCK variants at the international level.
Keywords Glucokinase · Monogenic diabetes · DNA sequencing · Genetics
Abbreviations
PVS Pathogenic very strong
PS Pathogenic strong
PM Pathogenic moderate
PP Pathogenic supporting
FHx Family history
AR Autosomal recessive
del/ins Deletion/insertion
IFG Impaired fasting glucose
OGTT Oral glucose tolerance test
Communicated by Massimo Federici, M.D.
Sunita M. C. De Sousa
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1 Adelaide Medical School, University of Adelaide, Adelaide, Australia
2 Endocrine & Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
3 Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, Australia
4 Department of Genetics & Molecular Pathology, SA Pathology, Adelaide, Australia
5 Flinders Medical School, Flinders University, Adelaide, Australia
6 Clinical Genomics, St Vincent’s Hospital, Darlinghurst, Australia
7 School of Medicine, University of New South Wales, Sydney, Australia
8 Discipline of Genomic Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
9 School of Medicine, University of Notre Dame, Sydney, Australia
10 Centre for Cancer Biology, an alliance between SA Pathology, University of South Australia, Adelaide, Australia
Tim Mori1,2 · Katsiaryna Prystupa2,3 · Klaus Straßburger1,2 · Marc Bonn2,4 · Oana Patricia Zaharia2,3,5 · Olaf Spörkel2,4 · Oliver Kuß1,2,6 · Michael Roden2,3,5 · Robert Wagner2,3,5
Received: 10 December 2024 / Accepted: 13 December 2024 / Published online: 17 January 2025 © The Author(s) 2025
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