Cone-Rod Dystrophy (CORDX3) via the CACNA1F 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
11125 CACNA1F 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11125CACNA1F81479 81479(x2) $890 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 backbone).

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

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

For Sanger Sequencing click here.

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

  • Dana Talsness, PhD

Clinical Features and Genetics

Clinical Features

Cone-rod dystrophy (CORD/CRD) is a rare hereditary retinal disorder with a worldwide prevalence of ~1 in 40,000. CRD is characterized by dysfunction or degeneration of cone photoreceptors with relative preservation of rod function in the initial stages. The most common symptoms are photophobia and epiphora in bright light, decreased visual acuity, and dyschromatopsia. Fundus changes may vary from mild pigment granularity to a distinct atrophic lesion in the central macula. As the disease progresses, degeneration of rod photoreceptors also occurs and leads to progressive night blindness and peripheral visual field loss (Hamel 2007).

Incomplete X-linked congenital stationary night blindness (CSNB2) is a recessive, non-progressive (stationary) retinal disorder characterized by night blindness moderate myopia, nystagmus, strabismus and electroretinogram abnormalities of the Schubert-Bornschein type. Female carriers usually do not show any clinical signs. (Wutz et al. 2002; Bech-Hansen et al. 1998; Boycott et al. 1993).

Aland Island eye disease (AIED), also known as Forsius-Eriksson ocular albinism, is an X-linked recessive retinal disease characterized by reduced visual acuity, mild red-green colour blindness, nystagmus, fundus hypopigmentation and foveal hypoplasia, astigmatism and progressive myopia. AIED symptoms have similarities with Ocular Albinism type 1. However, there is no misrouting of optic nerve fibers in AIED. Female carries may exhibit latent nystagmus and high myopia (Hawksworth et al. 1995; Jalkanen et al. 2007).

Genetics

Non syndromic CRD is genetically heterogeneous and exhibits autosomal dominant (ad), autosomal recessive (ar) and, rarely, X-linked (xl) inheritance (Hamel 2007). So far about 25 genes have been implicated in different forms of CRD (RetNet). One of the xl-CRD (CORDX3) causative genes, CACNA1F, encodes retina-specific voltage-dependent calcium channel alpha 1F subunit (Cav1.4) and is localized to the Xp11.23 region. CACNA1F is also responsible for CSNB2 and AIED (Jalkanen 2006; Doering et al. 2007). Clinically, CORDX3 and CSNB2 have some overlapping clinical features such as the range of visual acuities, myopic refraction, and the ERG abnormalities. However, they are distinguishable from each other in some cases. For instance, CORDX3 is progressive, has onset between 3 and 33 years, has no congenital nystagmus or hyperopic refraction, and has only low grade astigmatism (Jalkanen 2006). In contrast, CSNB2 is stationary, in severe cases is seen early in life, and congenital nystagmus, hyperopic refraction, and astigmatism can be seen. AIED and CSNB2 also have some overlapping phenotypes but AIED has some additional features such as progressive myopia, dyschromatopsia, iris trans-illumination defects, and foveal hypoplasia (Vincent et al. 2011).

Retina-specific CACNA1F is shown to have a specific functional role in visual processing (Naylor et al. 2000). Mouse mutant studies have shown that Cav1.4 calcium channel is crucial for the synaptic transmission at photoreceptor ribbon synapses (Morgans 2001). There are about hundred pathogenic variations in CACNA1F, which are associated with X-linked CORDX3, CSNB2 and AIED (Human Gene Mutation Database). A founder mutation in exon 27 of CACNA1F (c.3166dupC; p.Leu1056Profs*11) was identified Sixty-six male patients from 15 families of Mennonite ancestry (Boycott et al. 2000). A CACNA1F mutation screening in a large Finnish family (seven affected males, 10 carrier females, and 33 unaffected family members) identified a splice site variant, which co-segregated with the disease phenotype and not found in 200 control chromosomes (Jalkanen 2006). While gross deletions have also been reported, the percentage of cases due to gross deletions is unknown at this time (Human Gene Mutation Database).

Clinical Sensitivity - Sequencing with CNV PGxome

Approximately 55% of X-Linked Congenital Stationary Night Blindness cases are due to mutations in CACNA1F gene (CSNB2) and the rest (45%) are caused by mutations in the NYX gene (CSNB1) (Boycott et al. 1993). Exome sequencing of 47 Chinese families with CORD identified CACNA1F mutations in ~2% (1/47) of their patient population (Huang et al. 2013).

Testing Strategy

This test provides full coverage of all coding exons of the CACNA1F 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

All patients with symptoms suggestive of CORDX3, CSNB2 and AIED, and apparent X-linked inheritance.

Gene

Official Gene Symbol OMIM ID
CACNA1F 300110
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Bech-Hansen NT, Naylor MJ, Maybaum TA, Pearce WG, Koop B, Fishman GA, Mets M, Musarella MA, Boycott KM. 1998. Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nat. Genet. 19: 264–267. PubMed ID: 9662400
  • Boycott KM, Pearce WG, Bech-Hansen NT. 2000. Clinical variability among patients with incomplete X-linked congenital stationary night blindness and a founder mutation in CACNA1F. Can. J. Ophthalmol. 35: 204–213. PubMed ID: 10900517
  • Boycott KM, Sauvé Y, MacDonald IM. 1993. X-Linked Congenital Stationary Night Blindness. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle,. PubMed ID: 20301423
  • Doering CJ, Peloquin JB, McRory JE. 2007. The Cav1. 4 calcium channel: more than meets the eye. Channels 1: 4–11. PubMed ID: 19151588
  • Hamel CP. 2007. Cone rod dystrophies. Orphanet J Rare Dis 1;2:7. PubMed ID: 17270046
  • Hawksworth NR, Headland S, Good P, Thomas NS, Clarke A. 1995. Aland island eye disease: clinical and electrophysiological studies of a Welsh family. Br J Ophthalmol 79: 424–430. PubMed ID: 7612552
  • Huang L, Zhang Q, Li S, Guan L, Xiao X, Zhang J, Jia X, Sun W, Zhu Z, Gao Y, Yin Y, Wang P, et al. 2013. Exome Sequencing of 47 Chinese Families with Cone-Rod Dystrophy: Mutations in 25 Known Causative Genes. PLoS ONE 8: e65546. PubMed ID: 23776498
  • Human Gene Mutation Database (Bio-base).
  • Jalkanen R, Bech-Hansen NT, Tobias R, Sankila E-M, Mantyjarvi M, Forsius H, Chapelle A de la, Alitalo T. 2007. A Novel CACNA1F Gene Mutation Causes Aland Island Eye Disease. Investigative Ophthalmology & Visual Science 48: 2498–2502. PubMed ID: 17525176
  • Jalkanen R. 2006. X linked cone-rod dystrophy, CORDX3, is caused by a mutation in the CACNA1F gene. Journal of Medical Genetics 43: 699–704. PubMed ID: 16505158
  • Morgans CW. 2001. Localization of the α1F calcium channel subunit in the rat retina. Investigative ophthalmology & visual science 42: 2414–2418. PubMed ID: 11527958
  • Naylor MJ, Rancourt DE, Bech-Hansen NT. 2000. Isolation and characterization of a calcium channel gene, Cacna1f, the murine orthologue of the gene for incomplete X-linked congenital stationary night blindness. Genomics 66: 324–327. PubMed ID: 10873387
  • Vincent A, Wright T, Day MA, Westall CA, Héon E. 2011. A novel p. Gly603Arg mutation in CACNA1F causes \AAland island eye disease and incomplete congenital stationary night blindness phenotypes in a family. Molecular vision 17: 3262. PubMed ID: 22194652
  • Wutz K, Sauer C, Zrenner E, Lorenz B, Alitalo T, Broghammer M, Hergersberg M, Chapelle A de L, Weber BHF, Wissinger B, Meindl A, Pusch CM. 2002. Thirty distinct CACNA1F mutations in 33 families with incomplete type of XLCSNB and Cacna1f expression profiling in mouse retina. European Journal of Human Genetics 10: 449–456. PubMed ID: 12111638

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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