Neurohypophyseal Diabetes Insipidus and Nephrogenic Diabetes Insipidus Panel

Diabetes Insipidus is characterized by polyuria and polydipsia. Inherited Diabetes Insipidus can be further divided into Neurohypophyseal Diabetes Insipidus, called Central Diabetes Insipidus (CDI), and Nephrogenic Diabetes Insipidus (NDI), respectively.

CDI is a neuroendocrine disorder resulting from deficiency of the antidiuretic hormone, also called arginine vasopressin, a hormone with the primary function of regulating the kidneys to retain water balance. The disease is characterized by polyuria and polydipsia. Patients may also show dehydration, vomiting, constipation, fever and development delay (Di Lorgi et al. 2012). CDI can be caused by pathogenic variants in the AVP gene.

NDI is a kidney disorder characterized by polyuria and polydipsia, which results from an insensitivity to vasopressin (also called antidiuretic hormone, ADH), a hormone that regulates the kidneys to retain water. Inherited Nephrogenic Diabetes Insipidus 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. NDI can be caused by pathogenic variants in the AVPR2 and AQP2 genes (Knoers 2012)

AVPR2 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. Inactivating pathogenic variants in the AVPR2 gene were shown to cause X-linked recessive NDI, which accounts for ~ 90% of inherited NDI, whereas activating pathogenics in the AVPR2 gene cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD), a rare disorder which can cause brain swelling and other serious complications due to low levels of salt in the blood (hyponatremia) (Knoers 2012). To date, more than 250 causative variants have been reported throughout the gene including missense (~50%), truncating, splice variants, or large deletions encompassing the entire AVPR2 gene (Knoers 2012, Human Gene Mutation Database). Approximately 8% of reported AVPR2 pathogenic variants are large deletions/duplications, which cannot be detected by Sanger Sequencing method (HGMD). Missense variants R137C or R137L were linked to NSIAD, while missense variant R137H was found in classic NDI (Feldman et al. 2005; Vandergheynst  et al. 2012). Recent data suggests that ~25% of females who are heterozygous carriers for AVPR2 pathogenic variants may show NDI symptoms (Sasaki et al. 2013).

AVP encodes the antidiuretic hormone arginine vasopressin (AVP), which is synthesized in the hypothalamus of brain. It binds to the vasopressin type 2 receptor (V2R) in the collecting ducts of the kidney and activates a series of reactions to regulate transepithelium water permeability in renal collecting tubes, which increases water reabsorption from urine and maintains the body’s water homeostasis (Babey et al. 2011). Pathogenic variants in AVP mainly cause autosomal dominant neurohypophyseal Diabetes Insipidus, however, a few pathogenic have been documented in families with an autosomal recessive form eurohypophyseal Diabetes Insipidus. To date, more than 70 pathogenic variants in AVP have been identified; They are missense (81%),  nonsense (10%), small del/ins (12%), one precoding point variant, and one large deletion including part of AVP (Human Gene Mutation Database; Christensen et al. 2013; Ilhan 2016).

AQP2 encodes the protein Aquaporin-2 in the renal collecting tubules, a member of water-transporting proteins, and plays key role in regulate water permeability in renal collecting tubes to maintain body’s water homeostasis. To date, more than 60 unique pathogenic variants have been identified in the AQP2 gene; the majority of them are missense (~85%), no large deletions have been reported (Knoers 2012, HGMD). Pathogenic variants in AQP2 cause both autosomal dominant and autosomal recessive NDI.

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

Analytical sensitivity may be high for AVP because all AVP pathogenic variants reported to date are expected to be detected by direct sequencing of genomic DNA. Clinical sensitivity is difficult to estimate due to the lack of documented cases.

AQP2 pathogenic variants can be detected by sequencing in about 10% of patients with clinical diagnosed nephrogenic diabetes insipidus (Knoers 2012).

Approximately 8% of reported AVPR2 pathogenic variants are large deletions/duplications, which cannot be detected by Sanger Sequencing (Human Gene Mutation Database). Only one large deletion including part of AVP has been reported (HGMD; Christensen et al. 2013) and no large deletions/duplications has been reported in AQP2 (HGMD).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).