Abstract: Objective  Congenital nephrogenic diabetes insipidus (CNDI) is a rare disease, the aim of this article is to help  better understanding of this disease. Methods The clinical features, genetic analysis and treatments of two siblings with CNDI  were retrospectively analyzed, and related literatures were reviewed. Results Both brothers had polydispia, polyuria and low  concentrate urine continuously, and they both had a mutation in AQP2 confirmmed with Sanger sequencing. This novel frame  shift mutation caused arginine of 254 to histidine, and prolonged AQP2 protein. Conclusions Gene analysis can help diagnosis  of CNDI. Amiloride is useful option for treatment.