年轻人的成熟型糖尿病(MODY)代表了单基因糖尿病(DM)的最常见形式,目前根据参与胰腺β细胞分化和功能的单基因突变分为14种不同的亚型。很大一部分MODY的病因不明,这表明遗传景观仍有待探索。最近,新的潜在MODY因果基因,参与β细胞的分化和功能,已经被确认,如RFX6,NKX2.2,NKX6.1,WFS1,PCBD1,MTOR,TBC1D4,CACNA1E,MNX1,AKT2,NEUROG3,EIF2AK3,GLIS3,HADH,PTF1A。MODY变异的遗传和临床特征仍然高度异质性,没有直接的基因型-表型相关性,尤其是低渗透剂亚型。这是对文献的叙述性回顾,旨在描述与MODY相关的新颖变体的最新技术。为了更深入地了解MODY的复杂性,我们还报道了一些关于一些众所周知的病理基因和MODY遗传模式的病因学作用的相关争议,以及MODY与自身免疫性糖尿病的罕见关联。由于可用数据有限,MODY相关基因的致病性评估仍然具有挑战性,特别是在稀有和低渗透亚型的背景下。考虑到准确诊断的重要性,MODY的预后和管理,需要更多的研究来进一步研究其遗传景观和基因型-表型相关性,以及非遗传修饰因子在这一组患者中的致病作用。
Maturity-onset diabetes of the young (MODY) represents the most frequent form of monogenic diabetes mellitus (DM), currently classified in 14 distinct subtypes according to single gene mutations involved in the differentiation and function of pancreatic β-cells. A significant proportion of MODY has unknown etiology, suggesting that the genetic landscape is still to be explored. Recently, novel potentially MODY-causal genes, involved in the differentiation and function of β-cells, have been identified, such as RFX6, NKX2.2, NKX6.1, WFS1, PCBD1, MTOR, TBC1D4, CACNA1E, MNX1, AKT2, NEUROG3, EIF2AK3, GLIS3, HADH, and PTF1A. Genetic and clinical features of MODY variants remain highly heterogeneous, with no direct genotype-phenotype correlation, especially in the low-penetrant subtypes. This is a narrative
review of the literature aimed at describing the current state-of-the-art of the novel likely MODY-associated variants. For a deeper understanding of MODY complexity, we also report some related controversies concerning the etiological role of some of the well-known pathological genes and MODY inheritance pattern, as well as the rare association of MODY with autoimmune diabetes. Due to the limited data available, the assessment of MODY-related genes pathogenicity remains challenging, especially in the setting of rare and low-penetrant subtypes. In consideration of the crucial importance of an accurate diagnosis, prognosis and management of MODY, more studies are warranted to further investigate its genetic landscape and the genotype-phenotype correlation, as well as the pathogenetic contribution of the nongenetic modifiers in this cohort of patients.