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Wolfram Syndrome Type 2 via the CISD2 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
CISD2 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
10045CISD281479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

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


  • Ben Dorshorst, PhD

Clinical Features and Genetics

Clinical Features

Wolfram Syndrome Type 2 is characterized by juvenile-onset diabetes mellitus, optic atrophy, high-frequency sensorineural hearing impairment, urinary tract dilatation, impaired renal function, hypogonadism, and severe gastrointestinal ulcer and bleeding, but not diabetes insipidus (Amr et al. 2007; Tranebjaerg et al. 2009).


The prevalence of CISD2-associated Wolfram syndrome type 2 is currently unknown. It does appear to be rare, being described in 4 consanguineous families with WFS like symptoms. The identification of a single homozygous missense mutation in affected individuals suggests an autosomal recessive mode of inheritance (El-Shanti et al. 2000). The exact function of the CISD2 protein is unknown, but limited studies suggest that it helps regulate mitochondrial function. Functional studies of the single pathogenic missense mutation identified in CISD2 results in an abnormally small, nonfunctional CISD2 protein that impairs mitochondrial function. This leads to decreased energy within the cells followed by cell death, particularly in cells of high energy demand such as nerve cells in the brain, eyes, or gastrointestinal tract.

Clinical Sensitivity - Sequencing with CNV PGxome

Current literature on CISD2-associated WFS2 suggests a single homozygous missense mutation at c.109G>C [Glu37Gln] as causative of disease (El-Shanti et al. 2000). No other causative mutations have been identified.

Testing Strategy

This test provides full coverage of all coding exons of the CISD2 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

The following are criteria sensitive and specific for WFS (Barrett et al 1995): juvenile-onset (before age 15 years) diabetes mellitus, juvenile-onset optic atrophy, sensorineural hearing impairment (which can sometimes be congenital and severe), ataxia, dementia/ intellectual disability (both may occur, but intellectual disability is rare), psychiatric disease and autosomal recessive inheritance. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in CISD2.


Official Gene Symbol OMIM ID
CISD2 611507
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Wolfram Syndrome 2 AR 604928


  • Amr S, Heisey C, Zhang M, Xia X-J, Shows KH, Ajlouni K, Pandya A, Satin LS, El-Shanti H, Shiang R. 2007. A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2. Am. J. Hum. Genet. 81: 673–683. PubMed ID: 17846994
  • Barrett TG, Poulton K, Bundey S. 1995. DIDMOAD syndrome; further studies and muscle biochemistry. J. Inherit. Metab. Dis. 18: 218–220. PubMed ID: 7564251
  • El-Shanti H, Lidral AC, Jarrah N, Druhan L, Ajlouni K. 2000. Homozygosity mapping identifies an additional locus for Wolfram syndrome on chromosome 4q. Am. J. Hum. Genet. 66: 1229–1236. PubMed ID: 10739754
  • Tranebjaerg L, Barrett T, Rendtorff ND. 2009. WFS1-Related Disorders. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301750


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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View Ordering Instructions

1) Select Test Method (Platform)

1) Select Test Type

2) Select Additional Test Options

No Additional Test Options are available for this test.

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