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Pseudohypoaldosteronism Type II Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
CUL3 81479,81479
KLHL3 81479,81479
WNK1 81479,81479
WNK4 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10181Genes x (4)81479 81479(x8) $990 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 Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

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


Genetic Counselors


  • Angela Gruber, PhD

Clinical Features and Genetics

Clinical Features

Pseudohypoaldosteronism type II (PHAII) is a rare monogenic disorder of renal electrolyte handling characterized by hypertension (due to increased renal salt reabsorption), hyperkalaemia (due to reduced renal K+ excretion, despite normal glomerular filtration and aldosterone secretion) and metabolic acidosis (due to reduced renal H+ secretion) (Wilson et al. 2001; Boyden et al. 2012). PHAII has a range of disease severity and age at disease onset. It has been sub-classified into five subtypes in terms of genetic locus, and individual causative genes have been identified for four subtypes.

Pseudohypoaldosteronism type IIB (OMIM# 614491) and IIC (OMIM# 614492) are caused by defects in WNK4 and WNK1 respectively, both of which encode WNK kinases. WNK kinases-related PHAII usually develops at an average age in the twenties to thirties and represents the less severe end of disease spectrum compared with that caused by mutations in KLHL3 and CUL3.

Pseudohypoaldosteronism type IID (OMIM# 614495) is caused by defects in the KLHL3 gene. KLHL3-related PHAII usually develops at an average age in the late twenties. The disease severity of KLHL3-related PHAII is more than that caused by WNK defects (WNK1 and WNK4) while much less than that caused by the CUL3 mutations.

Pseudohypoaldosteronism type IIE (OMIM# 614496) is caused by defects in CUL3. CUL3-related PHAII develops at an average age of nine and represents the most severe end of disease spectrum.


In pseudohypoaldosteronism type II (PHAII), the KLHL3-related subtype can be inherited in an autosomal dominant or recessive manner while the other three subtypes are autosomal dominant disorders caused by defects in WNK1, WNK4 or CUL3 (Wilson et al. 2001; Boyden et al. 2012; Louis-Dit-Picard et al. 2012).

KLHL3 has 15 coding exons that encode a BTB-domain-containing kelch protein, which plays a key role in salt, water, potassium, and pH homeostasis. To date, documented pathogenic KLHL3 variants include missense substitutions (majority), splicing and nonsense mutations, and small indels (Human Gene Mutation Database). Recessive KLHL3 mutations spread throughout the coding regions whereas dominant KLHL3 mutations apparently cluster in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding.

WNK1 has 28 coding exons that encode a serine-threonine protein kinase, which is a key regulator of blood pressure. To date, all documented PHAII-related WNK1 mutations are large deletions in intron 1 that led to an overexpression of the gene (Wilson et al. 2001).

WNK4 has 19 coding exons that encode a serine-threonine protein kinase, which is expressed exclusively in the kidney and plays a key role in salt, water, potassium, and pH homeostasis. To date, all documented pathogenic WNK4 mutations are missense substitutions (Human Gene Mutation Database).

PHAII-related CUL3 mutations have been found predominantly de novo. CUL3 has 16 coding exons that encode a member of the cullin protein family. Notably, to date, all documented PHAII-related CUL3 mutations result in an aberrant splicing of exon 9 regardless of mutation location within the vicinity of this region (Human Gene Mutation Database).

Clinical Sensitivity - Sequencing with CNV PGxome

In a cohort of 52 pseudohypoaldosteronism type II (PHAII) families, 8 (~15%) and 16 families (~30%) were found to have recessive and dominant KLHL3 mutations, respectively (Boyden et al. 2012). In the same study, 5 families (about 10%) were found to have WNK4 mutations and 17 families (about 33%) were found to have CUL3 mutations (Boyden et al. 2012). No PHAII-related WNK1 mutations were found via Sanger sequencing because documented PHAII-causing WNK1 mutations are large deletions in intron 1, which cannot be detected by the current sequencing method (Wilson et al. 2001; Boyden et al. 2012).

The only documented PHAII-causing WNK1 pathogenic variants to date are large deletions in intron 1 (Wilson et al. 2001; Boyden et al. 2012).

No large deletions or duplications have been found in the CUL3, KLHL3 and WNK4 genes (Human Gene Mutation Database).

Testing Strategy

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).

Indications for Test

Candidates for this test are patients with pseudohypoaldosteronism type II. Testing is also indicated for family members of patients who have known mutations in each individual gene of this panel.


Official Gene Symbol OMIM ID
CUL3 603136
KLHL3 605775
WNK1 605232
WNK4 601844
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test



  • Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, Tikhonova IR, Bjornson R, Mane SM, Colussi G, Lebel M, Gordon RD, et al. 2012. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482: 98-102. PubMed ID: 22266938
  • Human Gene Mutation Database (Bio-base).
  • Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N, Pylypenko O, Beaurain G, Bonnefond A, Sand O, Simian C, Vidal-Petiot E, Soukaseum C, et al. 2012. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat. Genet. 44: 456-460, S1-3. PubMed ID: 22406640
  • Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, et al. 2001. Human hypertension caused by mutations in WNK kinases. Science 293: 1107-1112. PubMed ID: 11498583


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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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