Pediatric Endocrine and Diabetes Unit, Department of Pediatrics, University Hospitals of Geneva, Geneva, Switzerland.
Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Pediatr Diabetes. 2019 May;20(3):366-369. doi: 10.1111/pedi.12814. Epub 2019 Feb 17.
When diabetes is associated with congenital malformations, without autoimmune antibodies, a genetic cause is suspected. Here, we aimed to identify a defective gene that led to diabetes.
We performed an exome analysis of an index case and his healthy parents.
The child presented with childhood-onset diabetes, congenital hypopituitarism, cardiac malformation, and anal atresia. A DNA analysis revealed a heterozygous de novo pathogenic variant in the developmental transcription factor, forkhead box A2 (FOXA2). The mutation resided in the DNA-binding domain, which is highly conserved among species. Tridimensional molecular dynamics simulation modeling predicted an altered interaction between the mutated protein and DNA.
A defect in the FOXA2 DNA-binding domain was associated with childhood-onset diabetes and multiple congenital anomalies, which reflected the pleiotropic nature of the gene. This report extends the recently described phenotype of neonatal hypoglycemia to later-onset diabetes. We suggest to include FOXA2 analysis for neonatal hypoglycemia and to implement a long-term follow-up, particularly for the risk of diabetes.
当糖尿病与先天性畸形相关，而不存在自身抗体时，疑有遗传原因。在此，我们旨在鉴定导致糖尿病的缺陷基因。
我们对一名指数病例及其健康父母进行了外显子组分析。
患儿表现为儿童起病的糖尿病、先天性垂体功能减退、心脏畸形和肛门闭锁。DNA 分析显示发育转录因子叉头框 A2（FOXA2）的杂合新生致病性变异。该突变位于 DNA 结合域，在种间高度保守。三维分子动力学模拟建模预测突变蛋白与 DNA 的相互作用发生改变。
FOXA2 DNA 结合域的缺陷与儿童起病的糖尿病和多种先天性异常相关，反映了该基因的多效性。本报告将新生儿低血糖症的最近描述表型扩展至迟发性糖尿病。我们建议对新生儿低血糖症进行 FOXA2 分析，并实施长期随访，特别是糖尿病风险。
