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
10181 CUL3 81479,81479 Order Options and Pricing
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 $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.

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

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

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

EMAIL CONTACTS

Genetic Counselors

Geneticist

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.

Genetics

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.

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

Genes

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

Name
PGxome®

Citations

  • 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/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

View Ordering Instructions

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

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