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Leukoencephalopathy with Ataxia and Familial Hyperaldosteronism Type II via the CLCN2 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
15455 CLCN2 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15455CLCN281479 81479,81479 $890 Order Options and Pricing

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 backbone).

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

Turnaround Time

18 days on average for standard orders or 13 days 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Li Fan, MD, PhD, FCCMG, FACMG

Clinical Features and Genetics

Clinical Features

CLCN2-related leukoencephalopathy is a rare neurological disorder with childhood or adult onset. The major symptoms include mild cerebellar ataxia, chorioretinopathy with visual field defects, optic neuropathy, mild cognitive impairment, headaches, and male oligo-/azoospermia. The minor features include epilepsy, paroxysmal kinesigenic dyskinesia, mild spasticity, and auditory abnormalities. MRI image analysis shows abnormally low signal on T1-weighted images and abnormally high signal on T2-weighted images in the posterior limbs of the internal capsules, midbrain crura cerebri, and middle cerebellar peduncles. Phenotype is variable (Depienne et al. 2013. PubMed ID: 23707145; Zeydan et al. 2017. PubMed ID: 28746943).  

CLCN2-related familial hyperaldosteronism type II results from excess production of the adrenal steroid aldosterone with early onset before 20 years old. Patients present with features such as hypertension and headache. Laboratory findings include increased serum aldosterone, increased aldosterone:renin ratio, decreased renin, and hypokalemia (Scholl et al. 2018. PubMed ID: 29403011; Fernandes-Rosa et al. 2018. PubMed ID: 29403012).

As leukoencephalopathy and hyperaldosteronism can be caused by defects in many genes with variable and overlapping presentations, it is difficult to diagnose by clinical manifestation and image studies only. An accurate molecular diagnosis is critical for treatment, prognosis, and prediction of recurrence risk as well as future family planning.

Genetics

CLCN2-related leukoencephalopathy with ataxia is inherited in an autosomal recessive manner, whereas CLCN2-related familial hyperaldosteronism type II is inherited in an autosomal dominant manner. Pathogenic variants in CLCN2 include missense, nonsense, splicing, small deletions and duplications, and small indels. A complex DNA arrangement has also been reported (Human Gene Mutation Database). A few de novo variants have been reported (Xie et al. 2019. PubMed ID: 31054517; Fernandes-Rosa et al. 2018. PubMed ID: 29403012).

CLCN2 encodes a voltage-gated chloride channel. Pathogenic variants with loss of function cause brain intramyelinic edema and myelin vacuolation, leading to leukoencephalopathy. Variants with gain of function result in primary aldosteronism due to increased expression of aldosterone synthase and aldosterone production in adrenocortical cells. A mouse model with loss of function Clcn2−/− displayed leukodystrophy as well as early postnatal retinal and testicular degeneration. Another mouse model with gain of function (p.Gly24Asp variant) presented primary aldosteronism (Gaitán-Peñas et al. 2017. PubMed ID: 28905383; Fernandes-Rosa et al. 2018. PubMed ID: 29403012). CLCN2 has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Clinical Sensitivity - Sequencing with CNV PGxome

Pathogenic variants in CLCN2 are considered a rare cause of leukoencephalopathy. To date, CLCN2-related leukoencephalopathy has been reported or identified in 16 patients from 15 families (Min et al. 2021. PubMed ID: 26539602; updated in May 20, 2021). In more than 80 patients with unsolved early-onset primary aldosteronism, 8 patients were confirmed to have a heterozygous variant in CLCN2 (Scholl et al. 2018. PubMed ID: 29403011).

Testing Strategy

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

This test provides full coverage of all coding exons of the CLCN2 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).

Indications for Test

CLCN2 sequencing is recommended for patients suspected to have CLCN2-related leukoencephalopathy and familial hyperaldosteronism type II.

Gene

Official Gene Symbol OMIM ID
CLCN2 600570
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Depienne et al. 2013. PubMed ID: 23707145
  • Fernandes-Rosa et al. 2018. PubMed ID: 29403012
  • Gaitán-Peñas et al. 2017. PubMed ID: 28905383
  • Human Gene Mutation Database (Biobase).
  • Min et al. 2021. PubMed ID: 26539602
  • Online Gene Essentiality (OGEE).
  • Scholl et al. 2018. PubMed ID: 29403011
  • Xie et al. 2019. PubMed ID: 31054517
  • Zeydan et al. 2017. PubMed ID: 28746943

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.
  • 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


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

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

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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