Neurohypophyseal Diabetes Insipidus and Nephrogenic Diabetes Insipidus Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10137 AQP2 81404,81479 Order Options and Pricing
AVP 81479,81479
AVPR2 81404,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10137Genes x (3)81479 81404, 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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)

Genetics

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.

Clinical Sensitivity - Sequencing with CNV PGxome

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).

Testing Strategy

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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Candidates for this test are patients with symptoms consistent with autosomal dominant, autosomal recessive, or X-linked recessive inheritance of NDI, and the family members of patients who have known AQP2, AVP or AVPR2 mutations.

Genes

Official Gene Symbol OMIM ID
AQP2 107777
AVP 192340
AVPR2 300538
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Babey M. et al. 2011. Nature Reviews. Endocrinology. 7: 701-14. PubMed ID: 21727914
  • Christensen J.H. et al. 2013. Clinical Genetics. 83: 44-52. PubMed ID: 22168581
  • Di Iorgi N. et al. 2012. Hormone Research in Paediatrics. 77: 69-84. PubMed ID: 22433947
  • Feldman B.J. et al. 2005. The New England Journal of Medicine. 352: 1884-90. PubMed ID: 15872203
  • Human Gene Mutation Database (Bio-base).
  • Ilhan M. et al. 2016. Journal of Endocrinological Investigation. 39: 285-90. PubMed ID: 26208472
  • Knoers. 2012. Nephrogenic Diabetes Insipidus. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301356
  • Sasaki S. et al. 2013. Clinical and Experimental Nephrology. 17: 338-44. PubMed ID: 23150186
  • Vandergheynst F. et al. 2012. European Journal of Clinical Investigation. 42: 254-9. PubMed ID: 21834801

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

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2) Select Additional Test Options

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