Report of 33 novel AVPR2 mutations and analysis of 117 families with X-linked nephrogenic diabetes insipidus

X-linked nephrogenic diabetes insipidus (NDI) is a rare disease caused by m utations in the arginine vasopressin receptor 2 gene (AVPR2). Thirty-three novel AVPR2 mutations were identified in 62 families that were not included in our previous studies. This study describes the diversity of mutations o bserved in a total of 117 families, the number of affected people at the ti me of diagnosis, skewed X chromosome inactivation in severely affected fema les, the inferred parental origin of de novo mutations, and it provides est imates of incidence. Among 117 families, there were 82 different putative d isease-causing mutations. Based on haplotype analysis, it can be inferred t hat when the same AVPR2 mutation is identified in different families that w ere not known to be related, the mutations most likely arose independently. More than half of the families had only one affected male; two families pr esented with a severely affected female and no family history of NDI. A de novo mutation arose during oogenesis in the mother in 20% of isolated cases . The estimate of about 8.8 per million male live births of the incidence o f X-linked NDI in the province of Quebec, Canada may be representative of t he general population except in Nova Scotia and New Brunswick, where the in cidence is more than six times higher. Documentation of the diversity of mu tations will assist in revealing the full spectrum of clinical variation. D iscussion of genetic and population genetic aspects of X-linked NDI may con tribute to early diagnosis and treatment.