Nephrogenic diabetes insipidus caused by a novel missense variant (p.S127Y) in the AVPR2 gene

Abstract

Nephrogenic diabetes insipidus (NDI) is a rare disease, wherein the principal cells of the collecting duct of the kidney are refractory or less responsive to the antidiuretic hormone AVP, resulting in impaired urinary concentration (1). The main clinical manifestations include polyuria and polydipsia, but these symptoms are not often evident during the infantile period; therefore, affected infants often present with poor feeding, and growth and developmental delays. NDI pathogenesis is categorized into two forms: congenital and acquired forms, with approximately 90% of congenital cases being caused by loss of function variants in the arginine vasopressin receptor type 2 (AVPR2) gene and pathogenic variants in the aquaporin 2 (AQP2) gene being responsible for the remaining 10%. AVPR2 is located on the X chromosome (Xq28); therefore, NDI patients with a pathogenic variant in AVPR2 exhibit an X-linked recessive inheritance pattern (OMIM # 304800). In contrast, AQP2 is located on chromosome 12 (12q13), and both autosomal dominant and recessive inheritance patterns have been reported. Approximately 180 missense/nonsense variants have been reported in AVPR2 according to the Human Gene Mutation Database (HGMD) (http://archive.uwcm. ac.uk/uwcm/mg/hgmd0.html). Genotype-phenotype association analyses revealed that some of the pathogenic variants in AVPR2 are associated with partial NDI; thus, accumulation of information on underlying variants will help clarify the clinical characteristics of NDI patients. We report a case of NDI with a novel missense variant in AVPR2, which was categorized as likely pathogenic based on the ACMG/AMP standards and guidelines for interpretation of sequence variants (2).