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Retinitis Pigmentosa 35 (RP35) and Cone-Rod Dystrophy 10 (CORD10) via the SEMA4A 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
11661 SEMA4A 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11661SEMA4A81479 81479,81479 $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

Retinitis pigmentosa (RP; OMIM # 268000) represents a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4000 (Booij et al. J Med Genet 42 (11): e67, 2005). RP is clinically characterized by retinal pigment deposits visible on fundus examination, nyctalopia ("night blindness"), followed by progressive degeneration of the photoreceptors, which eventually leads to blindness (van Soest et al. Surv Ophthalmol 43(4):321-34, 1999). Cone rod dystrophies (CORDs/CRDs) are 10 times less common than RP (1/40,000) and are 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. Orphanet J Rare Dis 2:7, 2007).

Genetics

SEMA4A (Semaphorin; OMIM # 607292), which encodes a transmembrane protein, is predominantly expressed in the brain and eyes. During embryonic development, specifically when the photoreceptor outer segments elongate, SEMA4A is expressed in the inner retina and retinal pigment epithelium (RPE). It has been shown that disruption of SEMA4A in a mouse model results in retinal degeneration, attenuation of retinal blood vessels and depigmentation of the RPE (Rice et al. Invest Ophthalmol Vis Sci 45(8):2767–2777, 2004). Notably, SEMA4A has been shown to regulate two distinct endosomal-sorting pathways that are essential for the maintenance of homeostatic balance between RPEs and photoreceptors and to help in photoreceptor survival and phototransduction during the transition between daylight and darkness (Toyofuku et al. Genes Dev 26(8):816-829, 2012). So far, only missense mutations in SEMA4A have been identified to be causative for autosomal dominant retinal degenerations (RP35, OMIM # 6102832 and CORD10, OMIM # 610283 (Human Gene Mutation Database), which was supported by the structural modeling analyses of the c.1049T>G (p.Phe350Cys) mutation. This analysis revealed that the c.1049T>G mutation reduces the amino-acid side-chain volume and generates a hollow space in the protein interior, which affects the protein overall stability. Moreover, photoreceptor degeneration was rescued by SEMA4A gene supplementation in an animal model (Nojima et al. Nat Commun 4:1406, 2013).

Clinical Sensitivity - Sequencing with CNV PGxome

Mutational screening in 190 patients (135 with RP, 25 CORD and 30 with congenital blindness) in a Pakistani population identified two SEMA4A mutations in 8 probands (~4%), which were not identified in 100 control subjects (Abid et al. J Med Genet 43(4):378-381, 2006).

So far, no gross deletions or duplications have been reported in SEMA4A (Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the SEMA4A 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 RP and Cone-rod dystrophy, specifically patients with remarkable photoreceptor degeneration. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in SEMA4A.

Gene

Official Gene Symbol OMIM ID
SEMA4A 607292
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Cone-Rod Dystrophy 10 AR 610283
Retinitis Pigmentosa 35 AR, AD 610282

Citations

  • Abid, A. et al. (2006). "Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases." J Med Genet 43(4):378-381. PubMed ID: 16199541
  • Booij JC. 2005. Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa. Journal of Medical Genetics 42: e67–e67. PubMed ID: 16272259
  • Hamel CP. 2007. Cone rod dystrophies. Orphanet J Rare Dis 1;2:7. PubMed ID: 17270046
  • Human Gene Mutation Database (Bio-base).
  • Nojima, S. et al. (2013). "A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration." Nat Commun 4:1406. PubMed ID: 23360997
  • Rice, D.S. et al. (2004). "Severe retinal degeneration associated with disruption of semaphorin 4A." Invest Ophthalmol Vis Sci 45(8):2767-2777, 2004. PubMed ID: 15277503
  • Toyofuku, T. et al. (2012). "Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival." Genes Dev 26(8):816-829. PubMed ID: 22465952
  • Van Soest S., Westerveld A. 1999. Survey of ophthalmology. 43: 321-34. PubMed ID: 10025514

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.
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