Genetic Insights Into AVP Deficiency: Identification of a Novel AVP Variant and Compilation of a Curated Catalogue of Pathogenic Variants.

Central diabetes insipidus, or arginine vasopressin deficiency (AVP-D), is a rare disorder caused by insufficient release of antidiuretic hormone from the pituitary gland. The disease is characterised by severe polyuria and polydipsia, which, in rare cases, can be caused by variants in the AVP gene. The aim of the present study was to identify the genetic cause of AVP-D in two families and compile and discuss an updated and complete catalogue of variants in AVP associated with AVP-D. Two Danish families with autosomal dominant inheritance of symptoms indicating AVP-D were included, and probands underwent an arginine-stimulated copeptin test. Genetic testing included direct sequencing of the coding regions of AVP. HGMD professional, ClinVar, and literature mining combined with expert-assisted filtering and curation were applied to compile all pathogenic variants in AVP reported until now. Genetic analysis of the two probands, both of which had abnormally low levels of arginine-stimulated copeptin, and selected family members revealed co-segregation of AVP-D and heterozygosity for a novel pathogenic missense variant in AVP (c.122G>A, p.(Cys41Tyr)). This variant was included in an updated and curated list of 110 pathogenic AVP variants associated with AVP-D. These findings expand the known mutational spectrum of AVP and provide a consolidated resource to support clinical interpretation and future genotype-phenotype studies.