Nephrogenic Diabetes Insipidus (NDI) and Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) via the AVPR2 Gene

Nephrogenic Diabetes Insipidus (NDI) is a kidney disorder characterized by polyuria (too much urine) and polydipsia (excessive thirst), which results from an insensitivity to vasopressin (also called antidiuretic hormone, ADH), a hormone that regulates the kidneys to retain water.

Inherited NDI patients usually display early onset (< 1 year old), poor feeding, failure to thrive, fever and short stature, and are prone to severe dehydration trigged by illness, hot environments and water depletion. Inactivating mutations in the arginine vasopressin receptor gene (AVPR2) were shown to cause X-linked recessive NDI (OMIM#304800), which accounts for ~ 90% of inherited NDI, whereas activating mutations in the AVPR2 gene cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD) (OMIM#300539), a rare disorder which can cause brain swelling and other serious complications due to low levels of salt in the blood (hyponatremia) (Knoers, GeneReview 2012; Bichet et al. Prog Mol Biol Transl Sci, 89:15-29, 2009). Recent data suggests that ~25% of females who are heterozygous carriers for AVPR2 causative gene mutations have NDI symptoms (Sasaki et al., 2012).

Inherited NDI can be caused by mutations in the AVPR2 and AQP2 genes. AVPR2 (OMIM#300538) encodes arginine vasopressin receptor 2 (V2R), a member of G protein superfamily predominantly expressed in the kidney collecting ducts. Coupled with arginine vasopressin (AVP), V2R activates a series of reactions to regulate transepithelium water permeability in renal collecting tubes. This increases water reabsorption from urine and maintains body’s water homeostasis. To date, more than 200 causative mutations have been reported throughout the gene including missense (~50%), truncating, splice mutations, or large deletions encompassing the entire AVPR2 gene (Anesi et al, 2012). Missense mutations R137C or R137L were linked to NSIAD, while missense mutation R137H was found in classic NDI (Bichet et al, 2009).

AVPR2 causative gene mutations can be detected by sequencing in about 95% of patients with clinically diagnosed X-linked Nephrogenic diabetes insipidus (Knoers, GeneReview 2012).

Approximately 8% of reported AVPR2 pathogenic variants are large deletions/duplications, which cannot be detected by Sanger Sequencing (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the AVPR2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).