Russ-Silsby James, Teles Milena, Hassan Samar S, Elbarbary Nancy S, Ngọc Cấn Thị Bích, De Franco Elisa
Department of Clinical and Biomedical Science, University of Exeter Medical School, Exeter, UK.
Grupo de Diabetes Monogênico, Unidade de Endocrinologia Genética (LIM25), Unidade de Diabetes, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
Diabetologia. 2025 Jul 16. doi: 10.1007/s00125-025-06495-3.
Monogenic forms of diabetes represent an uncommon but very heterogeneous subset of the disease, with variable associated clinical features and key differences in treatment options. In this review, we discuss how advances in precision medicine and genomic sequencing have enhanced our understanding of the aetiology and clinical variability of monogenic diabetes. We highlight current global challenges, including the over-representation of individuals of European genetic ancestry in research studies, which complicates diagnosis in non-European populations, and national disparities in genetic testing strategies, which influence diagnostic accuracy. Additionally, we address issues in variant interpretation stemming from the increased understanding of variable penetrance in monogenic diabetes and the need to expand current reference datasets to exclude common genetic variation. Finally, we explore future directions, including the potential benefits of ongoing genetic studies for under-represented populations, the benefits and potential pitfalls of newborn screening programmes, and the potential of stem cell-derived islet transplantation and glucagon-like peptide- 1 receptor agonists as treatments for some forms of monogenic diabetes.
单基因糖尿病是该疾病中一个罕见但非常异质的亚型，具有多样的相关临床特征和治疗选择上的关键差异。在本综述中，我们讨论了精准医学和基因组测序的进展如何增进了我们对单基因糖尿病病因及临床变异性的理解。我们强调了当前全球面临的挑战，包括研究中欧洲遗传血统个体的过度代表性，这使得非欧洲人群的诊断变得复杂，以及遗传检测策略的国家差异，这影响了诊断准确性。此外，我们还讨论了由于对单基因糖尿病可变外显率的进一步了解以及需要扩大当前参考数据集以排除常见遗传变异而导致的变异解读问题。最后，我们探讨了未来的方向，包括正在进行的针对代表性不足人群的基因研究的潜在益处、新生儿筛查项目的益处和潜在陷阱，以及干细胞衍生的胰岛移植和胰高血糖素样肽-1受体激动剂作为某些形式单基因糖尿病治疗方法的潜力。
