Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Endocrinology, The First People's Hospital of Foshan, Foshan, China.
J Diabetes Investig. 2024 Jan;15(1):121-130. doi: 10.1111/jdi.14084. Epub 2023 Sep 22.
HNF1B syndrome is caused by defects in the hepatocyte nuclear factor 1B (HNF1B) gene, which leads to maturity-onset diabetes of the young type 5 and congenital organ malformations. This study aimed to identify a gene defect in a patient presenting with diabetes and severe diarrhea, while also analyzing the prevalence of hypomagnesemia and its correlation with the HNF1B genotype.
Whole exome sequencing was used to identify responsible point mutations and small indels in the proband and their family members. Multiplex ligation-dependent probe amplification was carried out to identify HNF1B deletions. Furthermore, an analysis of published data on 539 cumulative HNF1B cases, from 29 literature sources, was carried out to determine the correlation between the HNF1B genotype and the phenotype of serum magnesium status.
Using multiplex ligation-dependent probe amplification, we identified a de novo heterozygous HNF1B deletion in the patient, who showed dorsal pancreas agenesis and multiple kidney cysts, as detected by magnetic resonance imaging. Magnesium supplementation effectively alleviated the symptoms of diarrhea. Hypomagnesemia was highly prevalent in 192 out of 354 (54.2%) patients with HNF1B syndrome. Compared with patients with intragenic mutations, those with HNF1B deletions were more likely to suffer from hypomagnesemia, with an odds ratio of 3.1 (95% confidence interval 1.8-5.4).
Hypomagnesemia is highly prevalent in individuals with HNF1B syndrome, and those with HNF1B deletion are more susceptible to developing hypomagnesemia compared with those with intragenic mutations. The genotype-phenotype associations in HNF1B syndrome have significant implications for endocrinologists in terms of genotype detection, treatment decisions and prognosis assessment.
HNF1B 综合征是由肝细胞核因子 1B（HNF1B）基因缺陷引起的，可导致青年发病的成年型糖尿病 5 型和先天性器官畸形。本研究旨在鉴定一位同时患有糖尿病和严重腹泻的患者的基因缺陷，并分析低镁血症的患病率及其与 HNF1B 基因型的相关性。
采用外显子组测序鉴定先证者及其家系中致病变异和小片段插入/缺失。采用多重连接依赖探针扩增检测 HNF1B 缺失。此外，还分析了 29 项文献中 539 例 HNF1B 病例的已有数据，以确定 HNF1B 基因型与血清镁状态表型之间的相关性。
采用多重连接依赖探针扩增，我们在该患者中鉴定出一个新发生的 HNF1B 杂合缺失，该患者经磁共振成像显示背侧胰腺发育不全和多个肾囊肿。补充镁剂可有效缓解腹泻症状。在 192 例 HNF1B 综合征患者中有 354 例（54.2%）存在低镁血症。与存在基因内突变的患者相比，HNF1B 缺失的患者更易发生低镁血症，比值比为 3.1（95%置信区间 1.8-5.4）。
HNF1B 综合征患者中低镁血症的患病率很高，与存在基因内突变的患者相比，HNF1B 缺失的患者更易发生低镁血症。HNF1B 综合征中的基因型-表型关联对内分泌科医生在基因型检测、治疗决策和预后评估方面具有重要意义。
