Marucci Antonella, Menzaghi Claudia, Dodesini Alessandro Roberto, Albizzi Mascia, Acquafredda Angelo, Fini Grazia, Trischitta Vincenzo, Paola Rosa Di
Research Unit of Diabetes and Endocrine Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Foggia, 71013, Italy.
Endocrine and Diabetology Unit, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, 24127, Italy.
Acta Diabetol. 2025 Mar;62(3):323-328. doi: 10.1007/s00592-024-02357-3. Epub 2024 Aug 27.
Monogenic diabetes is one of the few examples in metabolic diseases in which a real precision medicine approach can be implemented in daily clinical work. Unfortunately, most of what is known today comes from studies in Whites, thus leaving much uncertainty about the genetics and the clinical presentation of monogenic diabetes in non-Europeans. To fill this gap, we report here two pedigrees from Bangladesh with CEL- and RFX6- diabetes, two rare types of monogenic diabetes which have never been described so far in individuals of the Indian subcontinent.
Next generation, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) were performed. Variants' interpretation was according to the American College of Medical Genetics and Genomics guidelines.
In the pedigree with CEL-diabetes, a large and never described deletion of exon 2-11 of CEL (confirmed by MLPA) affecting the entire catalytic domain and being likely pathogenic (LP) was observed in both the proband (who had diabetes at 16) and his mother (diabetes at 31), but not in relatives with normoglycemia. In the pedigree with RFX6-diabetes, a LP protein truncation variant (PTV, p.Tyr192*) in RFX6 was found in both the proband (diabetes at 9) and his mother (diabetes at 30), thus suggesting high heterogeneity in disease onset. Normoglycemic relatives were not available for genetic testing.
We report genetic features and clinical presentation of the first two cases of CEL- and RFX6-diabetes from the Indian subcontinent, thus contributing to fill the gap of knowledge on monogenic diabetes in non-Europeans.
单基因糖尿病是代谢性疾病中少数几个可在日常临床工作中实施真正精准医学方法的例子之一。不幸的是，目前已知的大多数信息都来自对白人的研究，因此对于非欧洲人群中单基因糖尿病的遗传学和临床表现仍存在很多不确定性。为填补这一空白，我们在此报告了来自孟加拉国的两个家系，分别患有CEL和RFX6相关糖尿病，这是两种罕见的单基因糖尿病类型，迄今为止在印度次大陆的个体中从未有过描述。
进行了下一代测序、桑格测序和多重连接依赖探针扩增（MLPA）。变异的解读依据美国医学遗传学与基因组学学会的指南。
在患有CEL相关糖尿病的家系中，先证者（16岁患糖尿病）及其母亲（31岁患糖尿病）均检测到CEL基因外显子2至11的一个大的、从未被描述过的缺失（经MLPA确认），该缺失影响整个催化结构域，可能具有致病性（LP），而血糖正常的亲属未检测到。在患有RFX6相关糖尿病的家系中，先证者（9岁患糖尿病）及其母亲（30岁患糖尿病）均发现RFX6基因中的一个LP蛋白截短变异（PTV，p.Tyr192*），这表明疾病发病存在高度异质性。没有血糖正常的亲属可供进行基因检测。
我们报告了印度次大陆首例两例CEL和RFX6相关糖尿病的遗传特征和临床表现，从而有助于填补非欧洲人群中单基因糖尿病的知识空白。
