Exome sequencing identifies a de novo FOXA2 variant in a patient with syndromic diabetes

Objective 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. Research Design and Methods We performed an exome analysis of an index case and his healthy parents. Results 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. Conclusions 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.