De Sousa Sunita M C, Phan Jennifer M N, Wells Amanda, Wu Kathy H C, Scott Hamish S
Adelaide Medical School, University of Adelaide, Adelaide, Australia.
Endocrine & Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia.
Acta Diabetol. 2025 Jan 16. doi: 10.1007/s00592-025-02449-8.
To assess the utility of reanalysing GCK variants of uncertain significance (VUS) as an intervention to improve the detection of monogenic diabetes.
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.
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.
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 GCK variants at the international level.
评估重新分析意义未明的GCK变异（VUS）作为一种改善单基因糖尿病检测的干预措施的效用。
我们在一个当地疑似单基因糖尿病个体队列中检测了GCK VUS，并根据最新的ClinGen GCK特异性变异分类指南重新整理了每个变异。
变异重新分析在8个已鉴定的VUS中有4个获得了新的“可能致病”分类（即阳性结果）。表明变异致病性的最常见新应用标准是确诊的GCK高血糖表型。对两个病例进行了RNA测序和家系研究，但对重新分类没有附加作用。
这是首次使用基因特异性指南对单基因糖尿病进行VUS重新分类的研究。在这项小型研究的范围内，我们观察到VUS升级为阳性结果的比例很高（50%），从而证实了VUS重新分析（特别是结合生化表型分析）在增加单基因糖尿病检测方面的效用。我们建议将糖化血红蛋白、空腹血糖以及胰腺自身抗体阴性或口服葡萄糖耐量试验小幅增加作为一个可行的最小数据集，以便在个体患者层面为变异分类提供信息，同时注意到ClinGen单基因糖尿病专家小组正在国际层面系统审查GCK变异的工作。
